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Study Question: What is the impact of the EuroNet-PHL-C2 treatment for boys with classical Hodgkin lymphoma (cHL) on semen parameters?, Summary Answer: More than half of the patients (52%, n = 16/31) had oligozoospermia or azoospermia at 2 years from cHL diagnosis; particularly boys treated for advanced-stage cHL had low sperm counts and motility., What Is Known Already: Chemotherapy and radiotherapy to the inguinal region or testes can impair spermatogenesis and result in reduced fertility. The EuroNet-PHL-C2 trial aims to minimize radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. The present study aims to assess the (gonadotoxic) impact of this treatment protocol on semen parameters and reproductive hormones in boys aged ≤18 years., Study Design, Size, Duration: This international, prospective, multi-centre cohort study was an add-on study to the randomized phase-3 EuroNet-PHL-C2 trial, where the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) was compared to intensified OEPA-DECOPDAC-21 chemotherapy (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide). Patients were recruited between January 2017 and September 2021., Participants/materials, Setting, Methods: Eligibility criteria included male patients, diagnosed with classical HL before or at the age of 18 years, and treated according to the EuroNet-PHL-C2 protocol in any of the 18 participating sites in the Netherlands, Germany, Belgium, Czech Republic, and Austria. Sperm parameters (sperm concentration, progressive motility, sperm volume, and calculated total motile sperm count) were assessed at diagnosis and 2 years after diagnosis in (post)pubertal boys. Laboratory measurements (serum follicle-stimulating hormone (FSH) and inhibin B) were performed in samples drawn at diagnosis, during treatment (2-3 times), and at 2 years post-diagnosis, and (age-adjusted) analyses were conducted separately for pre-pubertal and (post)pubertal boys. Outcomes were compared between the treatment levels (TL1, TL2, and TL3) and consolidation treatment schemes (COPDAC-28 and DECOPDAC-21)., Main Results and the Role of Chance: In total, 101 boys were included in the present analysis: 73 were (post)pubertal (median age 15.4 years, (IQR 14.4; 16.6), 10 TL1, 29 TL2, 34 TL3, 62% of TL2/3 patients received COPDAC-28) and 28 boys were pre-pubertal (median age 9.6 years (IQR 6.6; 11.4), 4 TL1, 7 TL2, 17 TL3, 38% of TL2/3 patients received COPDAC-28). The study included six boys who had received pelvic radiotherapy; none were irradiated in the inguinal or testicular area. At diagnosis, 48 (post)pubertal boys delivered semen for cryopreservation; 19 (40%) semen samples were oligospermic and 4 (8%) were azoospermic. Low sperm concentration (<15 mil/ml) appeared to be related to the HL disease itself, with a higher prevalence in boys who presented with B symptoms (76% vs 26%, aOR 2.3 (95% CI 1.0; 3.8), P = 0.001) compared to those without such symptoms. At 2 -years post-diagnosis, 31 boys provided semen samples for analysis, of whom 12 (39%) boys had oligozoospermia and 4 (13%) had azoospermia, while 22 boys (71%) had low total motile sperm counts (TMSC) (<20 mil). Specifically, the eight boys in the TL3 group treated with DECOPDAC-21 consolidation had low sperm counts and low progressive motility after 2 years (i.e. median sperm count 1.4 mil/ml (IQR <0.1; 5.3), n = 7 (88%), low sperm concentration, low median progressive motility 16.5% (IQR 0.0; 51.2), respectively). Age-adjusted serum FSH levels were significantly raised and inhibin B levels (and inhibin B:FSH ratios) were decreased during chemotherapy in (post)pubertal boys, with subsequent normalization in 80% (for FSH) and 60% (for inhibin B) of boys after 2 years. Only 4 out of the 14 (post)pubertal boys (29%) with low sperm concentrations after 2 years had elevated FSH (>7.6 IU/l), while 7 (50%) had low inhibin B levels (<100 ng/l). In pre-pubertal boys, reproductive hormones were low overall and remained relatively stable during chemotherapy., Limitations, Reasons for Caution: The present analyses included sperm and laboratory measurements up to 2 years post-diagnosis. Long-term reproductive outcomes and potential recovery of spermatogenesis remain unknown, while recovery was reported up to 5- or even 10-year post-chemotherapy in previous studies.Boys who were pre-pubertal at diagnosis were still too young and/or physically not able to deliver semen after 2 years and we could not assess a potential difference in gonadotoxicity according to pubertal state at the time of treatment. Overall, the statistical power of the analyses on sperm concentration and quality after 2 years was limited., Wider Implications of the Findings: Results of the semen analyses conducted among the 31 boys who had provided a semen sample at 2 years post-treatment were generally poor. However, additional long-term and adequately powered data are crucial to assess the potential recovery and clinical impact on fertility. The participating boys will be invited to deliver a semen sample after 5 years. Until these data become available, benefits of intensified chemotherapy in cHL treatment to reduce radiotherapy and lower risk for development of secondary tumours should be carefully weighed against potentially increased risk of other late effects, such as diminished fertility due to the increased chemotherapy burden. Boys with newly diagnosed cHL should be encouraged to deliver sperm for cryopreservation whenever possible. However, patients and clinicians should also realize that the overall state of disease and inflammatory milieu of cHL can negatively affect sperm quality and thereby reduce chance of successful fertility preservation. Furthermore, the measurement of FSH and inhibin B appears to be of low value in predicting low sperm quality at two years from cHL treatment., Study Funding/competing Interest(s): This study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M.-K., D.K., W.H.W., D.H., MC, A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors declare no potential conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Study Question: What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)?, Summary Answer: Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL., What Is Known Already: Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol., Study Design, Size, Duration: This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021., Participants/materials, Setting, Methods: Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses., Main Results and the Role of Chance: A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years., Limitations, Reasons for Caution: The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis., Wider Implications of the Findings: The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol., Study Funding/competing Interest(s): The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Purpose: The purpose of this study is to evaluate the use of fertility-preserving (FP) treatments and fertility counseling that was offered in a cohort of newly diagnosed children with classical Hodgkin lymphoma (cHL)., Methods: In this observational study, boys and girls with cHL aged ≤ 18 years with scheduled treatment according to the EuroNet-PHL-C2 protocol were recruited from 18 sites (5 countries), between January 2017 and September 2021. In 2023, a subset of Dutch participants (aged ≥ 12 years at time of diagnosis) and parents/guardians were surveyed regarding fertility counseling., Results: A total of 101 boys and 104 girls were included. Most post-pubertal boys opted for semen cryopreservation pre-treatment (85% of expected). Invasive FP treatments were occasionally chosen for patients at a relatively low risk of fertility based on scheduled alkylating agent exposure (4/5 testicular biopsy, 4/4 oocyte, and 11/11 ovarian tissue cryopreservation). A total of 17 post-menarchal girls (20%) received GnRH-analogue co-treatment. Furthermore, 33/84 parents and 26/63 patients responded to the questionnaire. Most reported receiving fertility counseling (97%/89%). Statements regarding the timing and content of counseling were generally positive. Parents and patients considered fertility counseling important (94%/87% (strongly agreed) and most expressed concerns about (their child's) fertility (at diagnosis 69%/46%, at present: 59%/42%)., Conclusion: Systematic fertility counseling is crucial for all pediatric cHL patients and their families. FP treatment should be considered depending on the anticipated risk and patient factors. We encourage the development of a decision aid for FP in pediatric oncology.

Background: Infertility is an important late effect of childhood cancer treatment. Ovarian tissue cryopreservation (OTC) is established as a safe procedure to preserve gonadal tissue in (pre)pubertal girls with cancer at high risk for infertility. However, it is unclear whether elective laparoscopic OTC can also be performed safely in infants <1 year with cancer. This systematic review aims to evaluate the reported risks in infants undergoing elective laparoscopy regarding mortality, and/or critical events (including resuscitation, circulatory, respiratory, neurotoxic, other) during and shortly after surgery., Methods: This systematic review followed the Preferred reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline. A systematic literature search in the databases Pubmed and EMbase was performed and updated on February 15 th , 2023. Search terms included 'infants', 'intubation', 'laparoscopy', 'mortality', 'critical events', 'comorbidities' and their synonyms. Papers published in English since 2000 and describing at least 50 patients under the age of 1 year undergoing laparoscopic surgery were included. Articles were excluded when the majority of patients had congenital abnormalities. Quality of the studies was assessed using the QUIPS risk of bias tool., Results: The Pubmed and Embase databases yielded a total of 12,401 unique articles, which after screening on title and abstract resulted in 471 articles to be selected for full text screening. Ten articles met the inclusion criteria for this systematic review, which included 1778 infants <1 years undergoing elective laparoscopic surgery. Mortality occurred once (death not surgery-related), resuscitation in none and critical events in 53/1778 of the procedures., Conclusion: The results from this review illustrate that morbidity and mortality in infants without extensive comorbidities during and just after elective laparoscopic procedures seem limited, indicating that the advantages of performing elective laparoscopic OTC for infants with cancer at high risk of gonadal damage may outweigh the anesthetic and surgical risks of laparoscopic surgery in this age group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 van der Perk, van der Kooi, Broer, Mensink, Bos, van de Wetering, van der Steeg and van den Heuvel-Eibrink.)

Purpose: To evaluate the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes., Methods: This study was embedded within the DCOG LATER-VEVO study; a Dutch, multicenter, retrospective cohort study between 2004 and 2014. Serum anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, antral follicle count (AFC), and self-reported (first) pregnancy outcomes were evaluated in female childhood HL survivors and controls., Results: 84 HL survivors and 798 controls were included, aged 29.6 and 32.7 years old at time of assessment. Median age at HL diagnosis was 13.4 years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000 mg/m 2 in 56 women and 14 survivors received pelvic irradiation. All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (< p10) 10.1 [95% CI 4.9; 20.6]; low AFC (< p10) 4.6 [95% CI 2.1; 9.9]; elevated FSH (> 10 IU/l) 15.3 [95% CI 5.7; 41.1], low Inhibin B (< 20 ng/l) 3.6 [ 95% CI 1.7; 7.7], p < 0.001). Pregnancy outcomes were comparable between survivors and controls (± 80% live birth, ± 20% miscarriage). However, survivors were significantly younger at first pregnancy (27.0 years vs 29.0 years, P = 0.04). Adjusted odds-ratio for time to pregnancy > 12 months was 2.5 [95% CI 1.1; 5.6] in survivors, p = 0.031. Adverse outcomes were specifically present after treatment with procarbazine and higher CED-score., Conclusion: HL survivors appear to have an impaired ovarian reserve. However, chance to achieve pregnancy seems reassuring at a young age. Additional follow-up studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic., (© 2023. The Author(s).)

Background: Turner syndrome (TS) is accompanied with premature ovarian insufficiency. Oocyte vitrification is an established method to preserve fertility. However, data on the oocyte yield in women with TS who vitrify their oocytes and the return rate to utilize the oocytes are scarce., Methods: Retrospective multicenter cohort study. Data was collected from medical records of women with TS who started oocyte vitrification between 2010 and 2021., Results: Thirty-three women were included. The median cumulative number of vitrified oocytes was 20 per woman. Complications occurred in 4% of the cycles. Significant correlations were found between the cumulative number of vitrified oocytes and AMH (r = 0.54 and p < 0.01), AFC (r = 0.49 and p < 0.01), percentage of 46,XX cells (r = 0.49 and p < 0.01), and FSH (r = -0.65 and p < 0.01). Spontaneous ( n = 8) and IVF ( n = 2) pregnancies occurred in 10 women ± three years after vitrification. So far, none of the women have returned to utilize their vitrified oocytes., Conclusions: Oocyte vitrification is a feasible fertility preservation option for women with TS, particularly in those with 46,XX cell lines or sufficient ovarian reserve. Multiple stimulation cycles are recommended to reach an adequate number of vitrified oocytes for pregnancy. It is too early to draw conclusions about the utilization of vitrified oocytes in women with TS.

Background: Owing to a growing number of young and adolescent Hodgkin lymphoma (HL) survivors, awareness of (long-term) adverse effects of anticancer treatment increases. The risk of impaired reproductive ability is of great concern given its impact on quality of life. There is currently no review available on fertility after childhood HL treatment., Objective and Rationale: The aim of this narrative review was to summarize existing literature on different aspects of reproductive function in male and female childhood, adolescent, and young adult HL survivors., Search Methods: PubMed and EMBASE were searched for articles evaluating fertility in both male and female HL survivors aged <25 years at diagnosis. In females, anti-Müllerian hormone (AMH), antral follicle count, premature ovarian insufficiency (POI), acute ovarian failure, menstrual cycle, FSH, and pregnancy/live births were evaluated. In males, semen-analysis, serum FSH, inhibin B, LH, testosterone, and reports on pregnancy/live births were included. There was profound heterogeneity among studies and a lack of control groups; therefore, no meta-analyses could be performed. Results were presented descriptively and the quality of studies was not assessed individually., Outcomes: After screening, 75 articles reporting on reproductive markers in childhood or adolescent HL survivors were included. Forty-one papers reported on 5057 female HL survivors. The incidence of POI was 6-34% (median 9%; seven studies). Signs of diminished ovarian reserve or impaired ovarian function were frequently seen (low AMH 55-59%; median 57%; two studies. elevated FSH 17-100%; median 53%; seven studies). Most survivors had regular menstrual cycles. Fifty-one studies assessed fertility in 1903 male HL survivors. Post-treatment azoospermia was highly prevalent (33-100%; median 75%; 29 studies). Long-term follow-up data were limited, but reports on recovery of semen up to 12 years post-treatment exist. FSH levels were often elevated with low inhibin B (elevated FSH 0-100%; median 51.5%; 26 studies. low inhibin B 19-50%; median 45%; three studies). LH and testosterone levels were less evidently affected (elevated LH 0-57%, median 17%; 21 studies and low testosterone 0-43%; median 6%; 15 studies). In both sexes, impaired reproductive ability was associated with a higher dose of cumulative chemotherapeutic agents and pelvic radiotherapy. The presence of abnormal markers before treatment indicated that the disease itself may also negatively affect reproductive function (Females: AMH

Background: Childhood cancer patients often remain uninformed regarding their potential risk of gonadal damage. In our hospital we introduced a five step standard oncofertility care plan for all newly diagnosed female patients aiming to identify, inform and triage 100% of patients and counsel 100% of patients at high risk (HR) of gonadal damage. This observational retrospective study (PEARL study) evaluated the use of this standard oncofertility care plan in the first full year in a national cohort., Methods: The steps consist of 1)timely (preferably before start of gonadotoxic treatment) identification of all new patients, 2)triage of gonadal damage risk using a standardized gonadal damage risk stratification tool, 3)informing all patients and families, 4)counseling of a selected subset of girls, and 5) fertility preservation including ovarian tissue cryopreservation (OTC) in HR patients using amended Edinburgh criteria. A survey of the medical records of all girls newly diagnosed with cancer the first year (1-1-2019 until 31-12-2019) was conducted., Results: Of 261 girls, 228 (87.4%) were timely identified and triaged. Triage resulted in 151 (66%) low(LR), 32 (14%) intermediate(IR) and 45 (20%) high risk(HR) patients. Ninety-nine families were documented to be timely informed regarding gonadal damage risk. In total, 35 girls (5 LR, 5 IR, 25 HR) were counseled by an oncofertility expert. 16/25 HR patients underwent fertility preservation (1 ovariopexy + OTC, oocyte cryopreservation (1 with and 1 without OTC) and 13 OTC). Fertility preservation did not lead to complications or delay of cancer treatment in any patient., Conclusion: We timely identified and triaged most girls (88%) with cancer with a high risk of gonadal damage to be counseled for fertility preservation. We aim to optimize the oncofertility care plan and the standardized gonadal damage risk stratification tool based on this experience and these may be of value to other pediatric oncology centers., Competing Interests: The authors have declared that no competing interests exist.

Context: Anti-Müllerian hormone (AMH) levels are used worldwide as a screening tool for the duration of the female reproductive lifespan. Although AMH levels are associated with age at menopause, individual predictions of menopause with a single AMH measurement are unreliable., Objective: This study investigated whether individual AMH decline patterns can improve the prediction of menopause compared with a single measurement., Design: The study population comprised 2434 premenopausal women from the population-based Doetinchem Cohort Study. Participants were followed up every 5 years for a total of 20 years, and AMH was measured in 6699 plasma samples with the picoAMH assay. Longitudinal statistical modeling was combined with time varying Cox modeling, to integrate multiple AMH measurements per woman., Results: The mean age at menopause was 50 years, and 7.4% of the women who reached menopause during follow-up did so before age 45 years. For a 25-year-old, the AMH decline rate between ages 20 and 25 years increased the C-statistic of menopause prediction from 0.64 to 0.69. Beyond that age, the AMH decline rate did not improve predictions of menopause or early menopause. For women younger than age 30 years, for whom menopause prediction is arguably most relevant, the models underestimated the risk of early menopause., Conclusion: These results suggest that knowledge of the AMH decline rate does not improve the prediction of menopause. Based on the low discriminative ability and underestimation of the risk of early menopause, the use of AMH as a screening method for the timing of menopause cannot currently be advocated., (Copyright © 2019 Endocrine Society.)

Context: Anti-Müllerian hormone based (AMH) age at menopause predictions remain cumbersome due to predictive inaccuracy., Objective: To perform an Individual Patient Data (IPD) meta-analysis, regarding AMH based menopause prediction., Data Sources: A systematic literature search was performed using PubMed, Embase and Cochrane databases., Study Selection: Prospective cohort studies regarding menopause prediction using serum AMH levels were selected by consensus discussion., Data Selection: Individual cases were included if experiencing a regular cycle at baseline. Exclusion criteria were hormone use and gynecological surgery., Data Synthesis: 2596 women were included, 1077 experienced menopause. A multivariable Cox regression analysis assessed time to menopause (TTM) using age and AMH. AMH predicted TTM, however, added value on top of age was poor (age alone C-statistic 84%; age + AMH HR 0.66 95% CI 0.61-0.71, C-statistic 86%). Moreover, the capacity of AMH to predict early (≤45 years) and late menopause (≥55 years) was assessed. An added effect of AMH was demonstrated for early menopause (age alone C-statistic 52%; age + AMH HR 0.33, 95% CI 0.24-0.45, C-statistic 80%). A Weibull regression model calculating individual age at menopause revealed that predictive inaccuracy remained present and increased with decreasing age at menopause. Lastly, a check of non-proportionality of the predictive effect of AMH demonstrated a reduced predictive effect with increasing age., Conclusion: AMH was a significant predictor of TTM and especially of time to early menopause. However, individual predictions of age at menopause demonstrated a limited precision, particularly when concerning early age at menopause, making clinical application troublesome.

In order to study whether ovarian reserve tests (ORTs) can predict time to ongoing pregnancy, we conducted a prospective cohort study in a cohort of healthy pregnancy planners. A total of 102 pregnancy planners were followed for 1 year, or until ongoing pregnancy occurred, after cessation of contraceptives). A baseline measurement of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH) and antral follicle count (AFC) was conducted. At the end of follow-up, a semen analysis was performed and chlamydia antibody titres were assessed. A univariate prediction model demonstrated age and the AFC to be significantly capable of predicting time to pregnancy (hazard ratio 0.92, 95% CI 0.87-0.98, p = 0.01; 1.04, 95% CI 1.01-1.07, p = 0.02 respectively). In the multivariate model, however, correcting for female age, we found no predictive effect of AMH, basal FSH or the AFC for time to ongoing pregnancy (hazard ratios 1.43, 95% CI 0.84-2.46, p = 0.36; 0.96, 95% CI 0.86-1.06, p = 0.43; 1.03, 95% CI 1.00-1.07, p = 0.08, respectively). This was confirmed by the low C-statistic. We therefore concluded that baseline AMH, AFC or FSH levels do not predict time to ongoing pregnancy in a cohort of healthy pregnancy planners. These results limit the usability of these ORTs in the assessment of current fertility.

Introduction: In this prospective cohort study we aimed to investigate the hypothesis that fluctuations in anti-Müllerian hormone levels stem from fluctuations in the number of antral follicles., Material and Methods: Repeated measurements of anti-Müllerian hormone and antral follicles (follicles 2-8 mm) were performed in 44 women with a regular cycle, during one menstrual cycle. If our hypothesis that anti-Müllerian hormone fluctuations stem from fluctuations in the antral follicles is correct, a fluctuation in the antral follicles would result in an equal and parallel shift in anti-Müllerian hormone. Hence, the difference between antral follicles and anti-Müllerian hormone would remain constant over time. A mixed model analysis, assessing the stability between anti-Müllerian hormone and antral follicles, was performed using the difference between log antral follicles and log anti-Müllerian hormone. Cohen's D was calculated for the largest of fixed effects in order to assess stability in relative distance between antral follicles and anti-Müllerian hormone. To assess if fluctuation in anti-Müllerian hormone or antral follicles originated from between-subject fluctuation, or from within subject fluctuation, the intra-class correlation coefficient was calculated., Results: Mixed model analysis and Cohen's D (0.12) confirmed the stability of the difference between log antral follicles and log anti-Müllerian hormone and so confirmed our hypothesis. The good intra-class correlation coefficient (0.73) indicated a small contribution of within-subject variation to anti-Müllerian hormone fluctuations., Conclusions: Fluctuations in anti-Müllerian hormone levels parallel fluctuations in antral follicles, suggesting that anti-Müllerian hormone levels are closely linked to variation in the antral follicles. This knowledge adds to the basic understanding of the origin of anti-Müllerian hormone and could aid in interpretation of individual anti-Müllerian hormone levels., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

Study Question: Do ovarian reserve tests (ORTs) predict age at natural menopause (ANM) in a cohort of healthy women with a regular menstrual cycle?, Summary Answer: Of the ORTs researched, anti-Müllerian hormone (AMH) alone predicts age at menopause. However, its predictive value decreased with increasing age of the woman, prediction intervals were broad and extreme ages at menopause could not be predicted., What Is Known Already: A fixed interval is hypothesized to exist between ANM and age at loss of natural fertility. Therefore, if it is possible to predict ANM, one could identify women destined for early menopause and thus at higher risk for age-related subfertility. Of ORTs researched in the prediction of ANM, AMH is the most promising one., Study Design, Study Size and Duration: A long-term, extended follow-up study was conducted, results of the first follow-up round were previously published. Two hundred and sixty-five normo-ovulatory women (21-46 years) were included between 1992 and 2001, 49 women (18.5%) could not be reached in the current follow-up round., Participants, Setting, Methods: Two hundred and sixty-five healthy normo-ovulatory women were included, recruited in an Academic hospital. We measured baseline AMH, follicle-stimulating hormone and the antral follicle count (AFC). At follow-up (2009 and 2013), menopausal status was determined via questionnaires. Cox regression analysis calculated time to menopause (TTM) using age and ORT. A check of (non-) proportionality of the predictive effect of AMH was performed. A Weibull survival model was used in order to predict individual ANM., Main Results and the Role of Chance: In total, 155 women were available for analyses. Eighty-one women (37.5%) had become post-menopausal during follow-up. Univariable Cox regression analysis demonstrated age and ORTs to be significantly correlated with TTM. Multivariable Cox regression analysis, adjusting for baseline age and smoking; however, demonstrated AMH alone to be an independent predictor of TTM (Hazard Ratio 0.70, 95% Confidence Interval 0.56-0.86, P-value <0.001). A (non-)proportionality analysis of AMH over time demonstrated AMH's predictive effect to decline over time., Limitations, Reason for Caution: The observed predictive effect of AMH became less strong with increasing age of the woman. Individual AMH-based age at menopause predictions did not cover the full range of menopausal ages, but did reduce the variation around the predicted ANM from 20 to 10.1 years., Wider Implications of the Findings: Age-specific AMH levels are predictive for ANM. Unlike in our previous publication however, a declining AMH effect with increasing age was observed. This declining AMH effect is in line with recent long-term follow-up data published by others. Moreover, the accompanying predictive inaccuracy observed in individual age at menopause predictions based on AMH, makes this marker currently unsuitable for use in clinical practice., Study Funding/competing Interests: No external funds were used for this study. M.D., M.J.C.E, S.L.B., G.J.S. and I.A.J.R. have nothing to declare. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, MSD, Organon, Serono and Schering Plough. F.J.M.B. receives monetary compensation: member of the external advisory board for Merck Serono, the Netherlands; consultancy work for Gedeon Richter, Belgium; educational activities for Ferring BV, the Netherlands; strategic cooperation with Roche on automated AMH assay development., (© The Author 2016. 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.)

Objective: This review aimed to appraise data on prediction of age at natural menopause (ANM) based on antimüllerian hormone (AMH), antral follicle count (AFC), and mother's ANM to evaluate clinical usefulness and to identify directions for further research., Methods: We conducted three systematic reviews of the literature to identify studies of menopause prediction based on AMH, AFC, or mother's ANM, corrected for baseline age., Results: Six studies selected in the search for AMH all consistently demonstrated AMH as being capable of predicting ANM (hazard ratio, 5.6-9.2). The sole study reporting on mother's ANM indicated that AMH was capable of predicting ANM (hazard ratio, 9.1-9.3). Two studies provided analyses of AFC and yielded conflicting results, making this marker less strong., Conclusions: AMH is currently the most promising marker for ANM prediction. The predictive capacity of mother's ANM demonstrated in a single study makes this marker a promising contributor to AMH for menopause prediction. Models, however, do not predict the extremes of menopause age very well and have wide prediction interval. These markers clearly need improvement before they can be used for individual prediction of menopause in the clinical setting. Moreover, potential limitations for such use include variations in AMH assays used and a lack of correction for factors or diseases affecting AMH levels or ANM. Future studies should include women of a broad age range (irrespective of cycle regularity) and should base predictions on repeated AMH measurements. Furthermore, currently unknown candidate predictors need to be identified.

Context: Menopause has been hypothesized to occur when the nongrowing follicle (NGF) number falls below a critical threshold. Age at natural menopause can be predicted using NGF numbers and this threshold. These predictions support the use of ovarian reserve tests, reflective of the ovarian follicle pool, in menopause forecasting., Objective: The objective of the study was to investigate the hypothesis that age-specific NGF numbers reflect age at natural menopause., Design and Setting: Histologically derived NGF numbers obtained from published literature (n = 218) and distribution of menopausal ages derived from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition (Prospect-EPIC) cohort (n = 4037) were combined., Participants: NGF data were from single ovaries that had been obtained postnatally for various reasons, such as elective surgery or autopsy. From the Prospect-EPIC cohort, women aged 58 years and older with a known age at natural menopause were selected., Interventions: There were no interventions., Main Outcome Measure(s): Conformity between observed age at menopause in the Prospect-EPIC cohort and NGF-predicted age at menopause from a model for age-related NGF decline constructed using a robust regression analysis. A critical threshold for NGF number was estimated by comparing the probability distribution of the age at which the NGF numbers fall below this threshold with the observed distribution of age at natural menopause from the Prospect-EPIC cohort., Results: The distributions of observed age at natural menopause and predicted age at natural menopause showed close conformity., Conclusion: The close conformity observed between NGF-predicted and actual age at natural menopause supports the hypothesis that that the size of the primordial follicle pool is an important determinant for the length of the individual ovarian life span and supports the concept of menopause prediction using ovarian reserve tests, such as anti-Müllerian hormone and antral follicle count, as derivatives of the true ovarian reserve.

Objective: This study aimed to cross-validate two comparable Weibull models of prediction of age at natural menopause from two cohorts, the Scheffer, van Rooij, de Vet (SRV) cohort and the Tehran Lipid and Glucose Study (TLGS) cohort. It summarizes advantages and disadvantages of the models and underlines the need for achieving correct time dependency in dynamic variables like anti-Müllerian hormone., Methods: Models were fitted in the original datasets and then applied to the cross-validation datasets. The discriminatory capacity of each model was assessed by calculating C-statistics for the models in their own data and in the cross-validation data. Calibration of the models on the cross-validation data was assessed by measuring the slope, intercept and Weibull shape parameter., Results: The C-statistic for the SRV model on the SRV data was 0.7 (95% confidence interval (CI) 0.7-0.8) and on the TLGS data it was 0.8 (95% CI 0.8-0.9). For the TLGS model on the TLGS data, it was 0.9 (95% CI 0.8-0.9) and on the SRV data it was 0.7 (95% CI 0.6-0.8). After calibration of the SRV model on the TLGS data, the slope was 1, the intercept -0.3 and the shape parameter 1.1. The TLGS model on the SRV data had a slope of 0.3, an intercept of 12.7 and a shape parameter of 0.6., Conclusions: Both models discriminate well between women that enter menopause early or late during follow-up. While the SRV model showed good agreement between the predicted risk of entering menopause and the observed proportion of women who entered menopause during follow-up (calibration) in the cross-validation dataset, the TLGS model showed poor calibration.

Background: In women, anti-Müllerian hormone (AMH) is exclusively produced by granulosa cells of ovarian follicles during the early stages of follicle development. After an initial increase until early adulthood, AMH concentrations slowly decrease with increasing age until becoming undetectable ∼5 years before menopause when the stock of primordial follicles is exhausted. However, major individual variability exists in the pace of follicle pool depletion and the initial size of the follicle pool, reflected by a wide range of age at menopause. Individual AMH serum concentration does accurately reflect the size of the pool of antral follicles, representing the quantity of the remaining primordial follicles. Accordingly, AMH levels may vary significantly in women of the same chronological age, allowing AMH to predict the remaining length of a woman's reproductive lifespan., Methods: Following 10 years of intense clinical research in this area (with over 300 papers published in core clinical journals every year), the level of evidence justifying use of AMH in ovarian reserve testing is rapidly increasing. We have conducted a summarizing review regarding all evidence published., Results: Many studies have convincingly demonstrated that AMH is the best currently available measure of ovarian reserve under a variety of clinical situations, such as infertility treatment (especially IVF), the forecasting of reproductive lifespan, ovarian dysfunction (especially polycystic ovary syndrome) and gonadotoxic cancer treatment or ovarian surgery. Moreover, AMH may help to individualize dosing for ovarian stimulation thereby improving the efficiency and safety of IVF. However, there are concerns about the performance of the AMH assay under different conditions regarding storage of samples and handling techniques. Therefore an international guideline for laboratories and a reference preparation are needed to make test results between laboratories truly comparable., Conclusions: AMH is the best current available measure of ovarian reserve for different clinical conditions. However, prospective well powered studies comparing different infertility treatment strategies based on initial AMH levels using appropriate end-points, such as live birth and cost-effectiveness, are urgently awaited. Such studies could represent a true step forward in rendering counseling and infertility care more patient tailored., (© The Author 2014. 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.)

Study Question: In the prediction of time to menopause (TTM), what is the added value of anti-Müllerian hormone (AMH) when mother's age at natural menopause (ANM) is also known?, Summary Answer: AMH is a more accurate predictor of individual TTM than mother's age at menopause., What Is Known Already: Mother's ANM is considered a proxy for daughter's ANM although studies on its predictive accuracy are non-existent. AMH is a biomarker with a known capacity to predict ANM. However, its added value on top of known predictors, like mother's ANM, is unknown., Study Design, Size, Duration: Population-based cohort studies were used. To assess any additive predictive value of mother's ANM, 164 mother-daughter pairs were used (Group 1). To assess the added value of AMH, a second group of 150 women in whom AMH and mother's ANM were recorded prior to a 12-year follow-up period during which daughter's ANM was assessed was used (Group 2)., Participants/materials, Setting, Methods: Group 1 consisted of participants of the DOM cohort (an ongoing breast cancer study). Group 2 was a pooled cohort of women with regular menstrual cycles from two independent published studies. Cox proportional hazards analysis estimated uni- and multivariate regression coefficients for female age at study entry, mother's ANM and AMH in the prediction of TTM. Discrimination of models was assessed with C-statistics. Clinical added value of AMH was quantified with a net reclassification index (NRI)., Main Results and the Role of Chance: A model with female age and mother's ANM had a c-statistic of 79 and 85% in groups 1 and 2, respectively. Both age and mother's ANM were significantly associated with TTM (HR 1.54 and HR 0.93 for age and mother's ANM in Cohort 1 and HR 1.59 and HR 0.89 in Group 2, respectively. P-value for all <0.001). In Group 2, the multivariate model with age, mother's ANM and AMH had a c-statistic of 92%, and only female age and AMH remained significantly associated with TTM (HR 1.41 P < 0.0001; HR 0.93 P = 0.08 and HR 0.06 P < 0.0001 for age, mother's ANM and AMH, respectively). The mean weighted NRI suggests that a 47% improvement in predictive accuracy is offered by adding AMH to the model of age and mother's ANM. In conclusion, AMH and mother's ANM both have added value in forecasting TTM for the daughter based on her age. In comparison, AMH is a more accurate added predictor of TTM than mother's ANM., Limitations, Reasons for Caution: The cohort of women is relatively small and different cohorts of women were pooled., Wider Implications of the Findings: This study shows that AMH is a more accurate predictor of ANM than mother's ANM. However, before achieving clinical applicability, the certainty with which a woman's prediction is made must improve. The association between mother's ANM and TTM in daughters did not appear to be influenced by whether ANM was recorded by mothers or daughters--an important finding because in the clinical setting daughters usually provide this information., Study Funding/competing Interest(s): No funding was received and there were no competing interests in direct relation to this study.

Objective: To evaluate whether ovarian reserve tests (ORTs) add prognostic value to patient characteristics, such as female age, in the prediction of excessive response to ovarian hyperstimulation in patients undergoing IVF, and whether their performance differs across clinical subgroups., Design: Authors of studies reporting on basal FSH, antimüllerian hormone (AMH), or antral follicle count (AFC) in relation to ovarian response to ovarian hyperstimulation were invited to share original data. Random intercept logistic regression models were used to estimate added value of ORTs on patient characteristics, while accounting for between-study heterogeneity. Receiver operating characteristic regression analyses were performed to study the effect of patient characteristics on ORT accuracy., Setting: In vitro fertilization clinics., Patient(s): A total of 4,786 women for the main analysis, with a subgroup of 1,023 women with information on all three ORTs., Intervention(s): None., Main Outcome Measure(s): Excessive response prediction., Result(s): We included 57 studies reporting on 32 databases. Female age had an area under the receiver operating characteristic curve of 0.61 for excessive response prediction. Antral follicle count and AMH significantly added prognostic value to this. A model with female age, AFC, and AMH had an area under the receiver operating characteristic curve of 0.85. The combination of AMH and AFC, without age, had similar accuracy. Subgroup analysis indicated that FSH performed significantly worse in predicting excessive response in higher age groups, AFC did significantly better, and AMH performed the same., Conclusion(s): We demonstrate that AFC and AMH add value to female age in the prediction of excessive response and that, for AFC and FSH, the discriminatory performance is affected by female age., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

BACKGROUND Although ovarian reserve tests (ORTs) are frequently used prior to IVF treatment for outcome prediction, their added predictive value is unclear. We assessed the added value of ORTs to patient characteristics in the prediction of IVF outcome. METHODS An individual patient data (IPD) meta-analysis from published studies was performed. Studies on FSH, anti-Müllerian hormone (AMH) or antral follicle count (AFC) in women undergoing IVF were identified and authors were contacted. Using random intercept logistic regression models, we estimated the added predictive value of ORTs for poor response and ongoing pregnancy after IVF, relative to patient characteristics. RESULTS We were able to collect 28 study databases, comprising 5705 women undergoing IVF. The area under the receiver-operating characteristic curve (AUC) for female age in predicting poor response was 0.61. AFC and AMH each significantly improved the model fit (P-value <0.001). Moreover, almost a similar accuracy was reached using AMH or AFC alone (AUC 0.78 and 0.76, respectively). Combining the two tests, however, did not improve prediction (AUC 0.80, P = 0.19) of poor response. In predicting ongoing pregnancy after IVF, age was the best single predictor (AUC 0.57), and none of the ORTs added any value. CONCLUSIONS This IPD meta-analysis demonstrates that AFC and AMH clearly add to age in predicting poor response. As single tests, AFC and AMH both fully cover the prediction of poor ovarian response. In contrast, none of the ORTs add any information to the limited capacity of female age to predict ongoing pregnancy after IVF. The clinical usefulness of ORTs prior to IVF will be limited to the prediction of ovarian response.

Context: It has been hypothesized that a fixed interval exists between age at natural sterility and age at menopause. Both events show considerable individual variability, with a range of 20 yr. Correct prediction of age at menopause could open avenues of individualized prevention of age-related infertility and other menopause-related conditions, like cardiovascular disease and breast carcinoma., Objective: The aim of this study was to explore the ability of ovarian reserve tests to predict age at menopause., Design and Setting: We conducted a long-term follow-up study at an academic hospital., Participants: A total of 257 normoovulatory women (age, 21-46 yr) were derived from three cohorts with highly comparable selection criteria., Interventions: Anti-Müllerian hormone (AMH), antral follicle count, and FSH were assessed at time 1 (T1). At time 2 (T2), approximately 11 yr later, cycle status (strictly regular, menopausal transition, or postmenopause) and age at menopause were inventoried., Main Outcome Measures: Accuracy of the ovarian reserve tests in predicting time to menopause was assessed by Cox regression, and a nomogram was constructed for the relationship between age-specific AMH concentrations at T1 and age at menopause., Results: A total of 48 (19%) women had reached postmenopause at T2. Age, AMH, and antral follicle count at T1 were significantly related with time to menopause (P < 0.001) and showed a good percentage of correct predictions (C-statistic, 0.87, 0.86, and 0.84, respectively). After adjusting for age, only AMH added to this prediction (C-statistic, 0.90). From the constructed nomogram, it appeared that the normal distribution of age at menopause will shift considerably, depending on the individual age-specific AMH level., Conclusions: AMH is highly predictive for timing of menopause. Using age and AMH, the age range in which menopause will subsequently occur can be individually calculated.

Background: Anti-Mullerian hormone (AMH) is a marker of ovarian reserve status and represents a good predictor of ovarian response to ovarian hyperstimulation. The aim of this study was to assess the accuracy of AMH and antral follicle count (AFC) as predictors of an excessive response in IVF/ICSI treatment., Methods: A systematic review and meta-analysis of the existing literature was performed. Studies were included if 2 × 2 tables for the outcome excessive response in IVF patients in relation to AMH/AFC could be constructed. Using a bivariate meta-analytic model, both summary point estimates for sensitivity and specificity were calculated, as well as summary ROC curves. Clinical value was analysed by calculating post-test probabilities of excessive response at optimal cut-off levels, as well as the corresponding abnormal test rates., Results: Nine studies reporting on AMH and five reporting on AFC were found. Summary estimates of sensitivity and specificity for AMH were 82 and 76%, respectively, and 82 and 80%, respectively, for AFC. Comparison of the summary estimates and ROC curves for AMH and AFC showed no statistical difference. Abnormal test rates for AMH and AFC amounted to ∼14 and 16%, respectively, at cut-off levels where test performance is optimal [likelihood ratio for a positive result (LR + ) > 8], with a post-test probability of ± 70%., Conclusions: Both AMH and AFC are accurate predictors of excessive response to ovarian hyperstimulation. Moreover, both tests appear to have clinical value. This opens ways to explore the potential of individualized FSH dose regimens based on ovarian reserve testing.

Objective: To assess the value of antimullerian hormone (AMH) as a test to predict poor ovarian response and pregnancy occurrence after IVF and to compare it with the performance of the antral follicle count (AFC)., Design: A systematic review of existing literature and a meta-analysis were carried out. After a comprehensive search, studies were included if 2 x 2 tables for outcomes poor response and pregnancy in IVF patients in relation to AMH or AFC could be constructed., Setting: Academic referral center for tertiary care., Patient(s): Cases indicated for IVF., Intervention(s): None., Main Outcome Measure(s): Poor response and nonpregnancy after IVF., Result(s): A total of 13 studies were found reporting on AMH and 17 on AFC. Because of heterogeneity among studies, calculation of a summary point estimate for sensitivity and specificity was not possible. However, for both tests summary receiver operating characteristic curves for the outcome measures poor response and nonpregnancy could be estimated and compared. The curves for the prediction of poor response indicated no significant difference between the performances of AMH and AFC. For the prediction of nonpregnancy, poor performance for both AMH and AFC was found., Conclusion(s): In this meta-analysis it was shown that AMH has at least the same level of accuracy and clinical value for the prediction of poor response and nonpregnancy as AFC.

Anti-Müllerian hormone (AMH) has important roles in postnatal ovarian function. Produced by ovarian granulosa cells, AMH is involved in initial follicle development. In fact, serum AMH level correlates with ovarian follicle number. In patients with polycystic ovary syndrome (PCOS), AMH levels are elevated, which indicates its potential relevance in PCOS diagnosis and management. AMH represents a useful clinical marker for the assessment of ovarian reserve in cases of subfertility caused by advanced age in women. A potential role for AMH in dominant follicle selection has also been suggested. Future challenges comprise the availability of a well-standardized assay and the development of AMH agonists and antagonists as possible tools to manipulate ovarian function for contraception or ovarian longevity.