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.

• Keywords
• anti-Müllerian hormone, chemotherapy, childhood Hodgkin lymphoma, gonadotoxicity, late effects, treatment-induced amenorrhea,
• MeSH
• Anti-Mullerian Hormone * blood   MeSH
• Cyclophosphamide therapeutic use   administration & dosage   MeSH
• Child MeSH
• Hodgkin Disease * blood   drug therapy   MeSH
• Humans MeSH
• Adolescent MeSH
• Prospective Studies MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   adverse effects   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Mullerian Hormone * MeSH
• Cyclophosphamide MeSH

Hypertension is the most prevalent cardiovascular disorder and the leading cause of death worldwide in both sexes. The prevalence of hypertension is lower in premenopausal women than in men of the same age, but sharply increases after the menopause, resulting in higher rates in women aged 65 and older. Awareness, treatment, and control of hypertension are better in women. A sex-pooled analysis from 4 community-based cohort studies found increasing cardiovascular risk beginning at lower systolic blood pressure thresholds for women than men. Hormonal changes after the menopause play a substantial role in the pathophysiology of hypertension in postmenopausal women. Female-specific causes of hypertension such as the use of contraceptive agents and assisted reproductive technologies have been identified. Hypertensive disorders in pregnancy are associated with increased risk of maternal, fetal, and neonatal morbidity and mortality, as well as with a greater risk of developing cardiovascular disease later in life. Hypertension-mediated organ damage was found to be more prevalent in women, thus increasing the cardiovascular risk. Sex differences in pharmacokinetics have been observed, but their clinical implications are still a matter of debate. There are currently no sufficient data to support sex-based differences in the efficacy of antihypertensive treatment. Adverse drug reactions are more frequently reported in women. Women are still underrepresented in large clinical trials in hypertension, and not all of them report sex-specific results. Therefore, it is of utmost importance to oblige scientists to include women in clinical trials and to consider sex as a biological variable.

• Keywords
• antihypertensive treatment, cardiovascular risk, contraceptive agents, epidemiology of hypertension, large clinical trials in hypertension, masked hypertension, polycystic ovary syndrome, white coat hypertension,
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1-5; 60 mg/m2 prednisone taken orally on days 1-15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

• MeSH
• Cyclophosphamide therapeutic use   MeSH
• Child MeSH
• Follicle Stimulating Hormone blood   MeSH
• Hodgkin Disease drug therapy   mortality   radiotherapy   MeSH
• Humans MeSH
• Adolescent MeSH
• Prednisone therapeutic use   MeSH
• Procarbazine therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Neoplasm Staging MeSH
• Vincristine therapeutic use   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH
• Names of Substances
• Cyclophosphamide MeSH
• Follicle Stimulating Hormone MeSH
• Prednisone MeSH
• Procarbazine MeSH
• Vincristine MeSH

Women undergo important changes in sex hormones throughout their lifetime that can impact cardiovascular disease risk. Whereas the traditional cardiovascular risk factors dominate in older age, there are several female-specific risk factors and inflammatory risk variables that influence a woman's risk at younger and middle age. Hypertensive pregnancy disorders and gestational diabetes are associated with a higher risk in younger women. Menopause transition has an additional adverse effect to ageing that may demand specific attention to ensure optimal cardiovascular risk profile and quality of life. In this position paper, we provide an update of gynaecological and obstetric conditions that interact with cardiovascular risk in women. Practice points for clinical use are given according to the latest standards from various related disciplines (Figure 1).

• Keywords
• Coronary artery disease, Female-specific risk factors, Hypertensive pregnancy disorders, Ischaemic heart disease, Menopausal hormone therapy, Menopause, Sexual health women, Transgender,
• MeSH
• Endocrinologists MeSH
• Cardiologists * MeSH
• Cardiovascular Diseases * epidemiology   etiology   MeSH
• Consensus MeSH
• Quality of Life MeSH
• Middle Aged MeSH
• Humans MeSH
• Menopause MeSH
• Risk Factors MeSH
• Aged MeSH
• Pregnancy MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

PURPOSE OF REVIEW: Many aspects of reproduction have been associated with increased blood pressure and impaired glucose metabolism that reveals a subsequent increased risk of cardiovascular disease. The aim of this review is to assess reproductive life factors associated with an increased risk of hypertension and cardiovascular disease, e.g., early life programming, sexual, and reproductive health in men and women. RECENT FINDINGS: Impaired fetal growth, with low birth weight adjusted for gestational age, has been found associated with hypertension in adulthood. Erectile dysfunction, currently considered an early diagnostic marker of cardiovascular disease preceding the manifestation of coronary artery disease by several years, frequently coexisting with hypertension, could also be exacerbated by some antihypertensive drugs. Male hypogonadism or subfertility are associated with increased cardiovascular risk. Hypertensive disorders in pregnancy including preeclampsia represent a major cause of maternal, fetal and neonatal morbidity, and mortality. The risk of developing preeclampsia can be substantially reduced in women at its high or moderate risk with a low dose of acetylsalicylic acid initiated from 12 weeks of gestation. An increased risk of hypertension in women following invasive-assisted reproductive technologies has been newly observed. Blood pressure elevation has been noticed following contraceptive pill use, around the menopause and in postmenopausal age. Furthermore, drug treatment of hypertension has to be considered as a factor with a potential impact on reproduction (e.g., due to teratogenic drug effects). In summary, a deeper understanding of reproductive life effects on hypertension and metabolic abnormalities may improve prediction of future cardiovascular disease.

• Keywords
• Assisted reproductive technologies, Erectile dysfunction, Hypertensive disorders in pregnancy, Low birth weight, Male hypogonadism, Oral contraception,
• MeSH
• Antihypertensive Agents MeSH
• Adult MeSH
• Hypertension * MeSH
• Cardiovascular Diseases * MeSH
• Humans MeSH
• Infant, Low Birth Weight MeSH
• Infant, Newborn MeSH
• Pre-Eclampsia * MeSH
• Reproductive Health * MeSH
• Pregnancy MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Antihypertensive Agents MeSH