A. Overbeek

Comparison of ovarian function markers in users of hormonal contraceptives during the hormone-free interval and subsequent natural early follicular phases

OBJECTIVE The aim of this study was to evaluate whether values of FSH, LH, estradiol, anti-Müllerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume (OV) determined on day 7 of the hormone-free interval are similar to values measured on days 2-5 of two subsequent natural menstrual cycles. In addition, values measured on day 7 of the hormone-free interval were examined for the purpose of predicting values measured on days 2-5 during the second natural cycle. METHODS In this study, 25 women using hormonal contraception provided a blood sample and underwent transvaginal ultrasound measurements on day 7 of the hormone-free interval and on cycle days 2-5 of two subsequent natural cycles. Changes were compared by repeated measures ANOVA and multivariate linear regression was used for prediction purposes. RESULTS Mean (SD) age of the participants was 26.3 (6.2) years. Overall significant decreases in FSH and inhibin B and significant increases in AMH, AFC and ovarian volume values were measured after discontinuation of hormonal contraception (P < 0.001, P = 0.04, P = 0.01, P < 0.001 and P = 0.004, respectively). Significant changes occurred both from day 7 of the hormone-free interval to natural cycle 1 as well as from natural cycle 1 to natural cycle 2. FSH, AMH and AFC values measured during days 2-5 of natural cycle 2 could be predicted by the corresponding values measured on day 7 of the hormone-free interval. CONCLUSION Hormonal and ultrasound markers of ovarian function in hormonal contraception users measured at the end of the hormone-free interval do not seem to represent subsequent natural early follicular phase values. However, these values can, in some cases (FSH, AMH and AFC), be used to predict early follicular phase values using calculated prediction equations, which need to be validated in future research.

Intra-cycle fluctuations of anti-Müllerian hormone in normal women with a regular cycle: a re-analysis

Anti-Müllerian hormone (AMH) has emerged as an important marker of ovarian reserve. Its variation throughout the cycle, however, may still be a matter of debate. The objective of this study was to re-evaluate the intra-cycle fluctuations of AMH in individuals in a prospective clinical study with focus on the age-related effects on these fluctuations. Frequent blood samples were obtained from the mid-luteal phase of the first cycle to the mid-luteal phase of the second cycle in 44 healthy, regularly menstruating Caucasian women. Main outcome measures were individual fluctuations of AMH concentrations during the natural menstrual cycle. AMH concentrations exhibited large fluctuations throughout the cycle and did not follow a defined pattern. Female age was negatively correlated with mean AMH concentrations. The absolute intra-individual variation was also negatively associated with age, whereas the relative intra-individual variation was positively associated with age. Although the fluctuation in relative intra-individual variation was higher in the older group, the absolute variation is very low and these fluctuations might therefore be of limited clinical relevance in this age group. These data show that in younger women caution should be exerted with the interpretation of a single randomly taken AMH measurement as a representative of ovarian reserve.

Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Ser-polymorphism in polycystic ovary syndrome

BACKGROUND Clomiphene citrate (CC) response in anovulatory women is difficult to predict and patient-tailored treatment would benefit patient care and time-management. The objective of this study was to evaluate the role of the follicle-stimulating hormone receptor (FSHR) Ser680Ser-polymorphism as a predictor for CC response. METHODS In this retrospective study, 193 patients, diagnosed with polycystic ovary syndrome (PCOS) according to Rotterdam criteria and treated with ovulation induction, were included over a 5-year period in a university hospital in the Netherlands. Data on demographics, BMI, menstrual cycle, laboratory screening (including FSHR genotyping), transvaginal ultrasonography of ovaries and ovulation parameters were collected. Main outcome measures were response to CC and FSHR genotype. RESULTS The frequency distribution of the 680-polymorphism was 26% (Asn/Asn), 50% (Asn/Ser) and 24% (Ser/Ser). No significant differences in basal characteristics were found. Significantly more patients with Ser/Ser-polymorphism were resistant to CC (28%) compared with Asn/Ser (14%) and Asn/Asn group (15%), with an odds ratio for ovulation of 0.44 (95% CI, 0.21-0.97). Patients with higher FSH levels, higher age and lower BMI were significantly more likely to ovulate in univariate analysis. In a multivariate logistic regression model, corrected for age, BMI, mean ovarian, volume, hyperandrogenism, and amenorrhoea, only FSHR and basal FSH levels were predictive for ovulation. CONCLUSIONS Chance of resistance to CC is almost double in women with PCOS harbouring the Ser/Ser genotype.

Frequency distribution of polymorphisms in the FSH receptor gene in infertility patients of different ethnicity

Studies on the frequency distribution of follicle-stimulating hormone receptor (FSHR) polymorphisms report conflicting results. It has been suggested that ethnicity might influence these outcomes. Therefore, the aim of this study was to determine the frequency distribution of FSHR polymorphisms at position 680 of exon 10 within a large group of women with fertility problems from different ethnic backgrounds. A total of 1771 women of different ethnic origin (Caucasian, Asian, Hindustani, Creole and Mediterranean) were studied. FSHR single-nucleotide polymorphisms at codon 680 of exon 10 were determined by restriction fragment length polymorphism of amplicons generated by polymerase chain reaction. Genotypes were compared with serum FSH concentrations and between different ethnic groups. A significantly lower number of Asians (10.5%) were found to have the Ser680Ser receptor variant compared with Caucasians (21.5%) and Mediterraneans (22.3%) (P=0.010). FSH concentrations did not differ between the various ethnic groups, or the different FSHR polymorphisms. In conclusion, the Ser680Ser receptor variant is less common in the Asian subgroup compared with Caucasians and Mediterraneans. This indicates that, when comparing allelic frequency distributions of the FSHR polymorphism variants, ethnic background should be accounted for. FSH concentrations did not differ between FSHR polymorphisms or between ethnic groups.

Using Web-Based and Paper-Based Questionnaires for Collecting Data on Fertility Issues Among Female Childhood Cancer Survivors: Differences in Response Characteristics

Background Web-based questionnaires have become increasingly popular in health research. However, reported response rates vary and response bias may be introduced. Objective The aim of this study was to evaluate whether sending a mixed invitation (paper-based together with Web-based questionnaire) rather than a Web-only invitation (Web-based questionnaire only) results in higher response and participation rates for female childhood cancer survivors filling out a questionnaire on fertility issues. In addition, differences in type of response and characteristics of the responders and nonresponders were investigated. Moreover, factors influencing preferences for either the Web- or paper-based version of the questionnaire were examined. Methods This study is part of a nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female childhood cancer survivors. The Web-based version of the questionnaire was available for participants through the Internet by means of a personalized user name and password. Participants were randomly selected to receive either a mixed invitation (paper-based questionnaire together with log-in details for Web-based questionnaire, n = 137) or a Web-only invitation (log-in details only, n = 140). Furthermore, the latter group could request a paper-based version of the questionnaire by filling out a form. Results Overall response rates were comparable in both randomization groups (83% mixed invitation group vs 89% in Web-only invitation group, P = .20). In addition, participation rates appeared not to differ (66% or 90/137, mixed invitation group vs 59% or 83/140, Web-only invitation group, P =.27). However, in the mixed invitation group, significantly more respondents filled out the paper-based questionnaire compared with the Web-only invitation group (83% or 75/90 and 65% or 54/83, respectively, P = .01). The 44 women who filled out the Web-based version of the questionnaire had a higher educational level than the 129 women who filled out the paper-based version (P = .01). Furthermore, the probability of filling out the Web-based questionnaire appeared to be greater for women who were allocated to the Web-only invitation group (OR = 2.85, 95% CI 1.31 - 6.21), were older (OR = 1.08, 95% CI 1.02 - 1.15), had a higher educational level (OR high vs low = 0.06, 95% CI 0.01 - 0.52), or were students (OR employed vs student = 3.25, 95% CI 1.00 - 10.56). Conclusions Although overall response as well as participation rates to both types of invitations were similar, adding a paper version of a questionnaire to a Web-only invitation resulted in more respondents filling out the paper-based version. In addition, women who were older, had a higher level of education, or were students, were more likely to have filled out the Web-based version of the questionnaire. Given the many advantages of Web-based over paper-based questionnaires, researchers should strongly consider using Web-based questionnaires, although possible response bias when using these types of questionnaires should be taken into account. Trial Registration Nederlands Trial Register NTR2922; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922 (Archived by WebCite at http://www.webcitation.org/5zRRdMrDv)

Malignant melanoma as second malignant neoplasm in long-term childhood cancer survivors: A systematic review†

This systematic review provides information on malignant melanoma as second malignant neoplasm (SMN) after childhood cancer and evaluates its risk factors. Study reports describing incidences of SMN and malignant melanoma as SMN in a population of childhood cancer survivors (CCS) were included. Of 151,575 CCS, 4,010 (2.6%) children developed an SMN, 212 of which were melanoma (5.3% or 0.14% of all CCS). The following risk factors for malignant melanoma as SMN were identified: radiotherapy, or the combination alkylating agents and anti‐mitotic drugs. Melanomas are most frequently observed after Hodgkin disease, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors. Pediatr Blood Cancer

A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges

BackgroundAdvances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study.MethodsThe study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements.DiscussionThe DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators.Trial registrationNTR2922; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922

Chemotherapy-related late adverse effects on ovarian function in female survivors of childhood and young adult cancer: A systematic review

BACKGROUND Anti-cancer treatment may reduce the fertile life span and induce premature menopause. This review aims to provide an overview of the available literature on effects of chemotherapy only on the incidence of ovarian dysfunction and to evaluate the relationship between dose of chemotherapy, age at time of treatment, and time since treatment in female survivors of childhood and young adult cancer. METHODS A comprehensive search of electronic databases was performed (search date December 2015). RESULTS 45 studies were included, describing, in total, 5607 female survivors. Median age at menopause was earlier in cancer survivors than in the general population. The prevalence of amenorrhoea varied from 0% to 83%. Those exposed to MVPP protocols were at highest risk for amenorrhoea (39-79%), as were breast cancer survivors receiving cyclophosphamide-containing regimens, in whom the prevalence of amenorrhoea was 40-80%. The most important risk factors for ovarian dysfunction were: (1) alkylating agents, specifically procarbazine and busulfan, (2) older age at treatment. CONCLUSION Breast cancer survivors, those treated with procarbazine or other alkylating agents and those with a higher age at diagnosis are at highest risk of diminished ovarian function. However, all studies included in this review showed methodological limitations. It is imperative that nation-wide registries guarantee long term follow-up during the adult life of cancer survivors.

Validity of self-reported data on pregnancies for childhood cancer survivors: a comparison with data from a nationwide population-based registry

STUDY QUESTION To what degree do records registered in the Netherlands Perinatal Registry (PRN) agree with self-report in a study questionnaire on pregnancy outcomes in childhood cancer survivors (CCSs)? SUMMARY ANSWER This study suggests that self-reported pregnancy outcomes of CCSs agree well with registry data and that outcomes reported by CCSs agree better with registry data than do those of controls. WHAT IS KNOWN ALREADY Many studies have shown that childhood cancer treatment may affect fertility outcomes in female CCSs; however, these conclusions were often based on questionnaire data, and it remains unclear whether self-report agrees well with more objective sources of information. STUDY DESIGN, SIZE, DURATION In an nationwide cohort study on fertility (inclusion period January 2008 and April 2011, trial number: NTR2922), 1420 CCSs and 354 sibling controls were invited to complete a questionnaire regarding socio-demographic characteristics and reproductive history. In total, 879 CCSs (62%) and 287 controls (81%) returned the questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS The current validation study compared the agreement between pregnancy outcomes as registered in the PRN and self-reported outcomes in the study questionnaire. A total of 589 pregnancies were reported in CCSs, and 300 pregnancies in sibling controls, of which 524 could be linked to the PRN. MAIN RESULTS AND THE ROLE OF CHANCE A high intra-class correlation coefficient (ICC) was found for birthweight (BW) (0.94 and 0.87 for CCSs and controls, respectively). The self-reported BWs tended to be higher than reported in the PRN. For gestational age (GA), the ICC was high for CCSs (0.88), but moderate for controls (0.49). CCSs overestimated GA more often than controls. The Kappa values for method of conception and for method of delivery were moderate to good. Multilevel analyses on the mean difference with regard to BW and GA showed no differences associated with time since pregnancy or educational level. LIMITATIONS, REASONS FOR CAUTION Not all pregnancies reported could be linked to the registry data. In addition, the completeness of the PRN could not be assessed precisely, because there is no information on the number of missing records. Finally, for some outcomes there were high proportions of missing values in the PRN registry. WIDER IMPLICATIONS OF THE FINDINGS Our study suggests that questionnaires are a reliable method of data collection, and that for most variables, self-report agrees well with registry data. STUDY FUNDING/COMPETING INTEREST This work was supported by the Dutch Cancer Society (grant no. VU 2006-3622) and by Foundation Children Cancer Free. None of the authors report a conflict of interest. TRIAL REGISTRATION NUMBER NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922.

Pharmacogenomics of ovulation induction: facilitating decisions on who, when and how to treat

response to clomiphene citrate is complex. Many have tried to find phenotypic factors that might inf luence the response to clomiphene [5–10]. However, to date no model has been proposed that can reliably predict outcome in ovulation induction with clomiphene citrate. Recently, we studied the relationship between a known polymorphism on the FSH receptor (p.N680S, rs6166) and clomiphene citrate resistance. In normal ovulatory women, this polymorphism results in different FSH levels within the normal range, pointing out a difference in sensitivity of the receptor [11]. It has been demonstrated that patients harboring the least sensitive variant (Ser/Ser) need higher doses of exogenous FSH for ovarian stimulation in ART [12–19]. In our data in women with PCOS, we could not find a difference in the FSH levels between different variants of the polymorphism, but found that the Ser/Ser variant was significantly more often present in women resistant to clomiphene citrate. This is probably caused by faulty feedback in the pituitary of PCOS patients. In women harboring the Ser/Ser-variant of the FSH receptor polymorphism, it is more difficult to overcome the FSH threshold after which follicle maturation start [20]. On the latest ESHRE congress in Amsterdam, data was presented showing that harboring the Ser/Ser variant of the FSH receptor polymorphism was significantly associated with a decreased chance of pregnancy when treated with clomiphene citrate [21]. For tamoxifen, a drug structurally much alike clomiphene citrate, pharmacogenomic data is accumulating. The same mechanisms that explain poor response to tamoxifen could be applicable for clomiphene citrate resistance (for example, CYP2D6 poly morphism) [22] and in this way might be a source for new hypotheses in the field of ovulation induction. If clomiphene citrate does not lead to ovulation (clomiphene resistance) or subsequent pregnancy (clomiphene failure), second-line Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility. Estimating its prevalence is difficult due to the different criteria that are used to diagnose this syndrome. According to the NIH criteria, diagnosis is based on the presence of chronic anovulation and clinical or biochemical signs of hyper androgenism [1]. In 2003, the Rotterdam European Society of Human Reproduction and Embryology (ESHRE)/American Society of Reproductive Medicine (ASRM)-Sponsored PCOS Consensus Workshop Group agreed to base the diagnosis on the presence of two of three possible features: clinical or biochemical hyperandro genism, oligoor an-ovulation, and the presence of polycystic ovaries on ultrasound examination [2]. The view of the Androgen Excess-PCOS Society Task Force is that PCOS should be defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries) and the exclusion of related disorders [3]. Due to this lack of consistency in phenotyping, PCOS is a heterogeneous syndrome, making tailored treatment difficult.