Curt W. Burger

Long-Term Psychological Impact of Carrying a BRCA1/2 Mutation and Prophylactic Surgery: A 5-Year Follow-Up Study

PURPOSE To explore long-term psychosocial consequences of carrying a BRCA1/2 mutation and to identify possible risk factors for long-term psychological distress. PATIENTS AND METHODS Five years after genetic test disclosure, 65 female participants (23 carriers, 42 noncarriers) of our psychological follow-up study completed a questionnaire and 51 participants were interviewed. We assessed general and hereditary cancer-related distress, risk perception, openness to discuss the test result with relatives, body image and sexual functioning. RESULTS Carriers did not differ from noncarriers on several distress measures and both groups showed a significant increase in anxiety and depression from 1 to 5 years follow-up. Carriers having undergone prophylactic surgery (21 of 23 carriers) had a less favorable body image than noncarriers and 70% reported changes in the sexual relationship. A major psychological benefit of prophylactic surgery was a reduction in the fear of developing cancer. Predictors of long-term distress were hereditary cancer-related distress at blood sampling, having young children, and having lost a relative to breast/ovarian cancer. Long-term distress was also associated with less open communication about the test result within the family, changes in relationships with relatives, doubting about the validity of the test result, and higher risk perception. CONCLUSION Our findings support the emerging consensus that genetic predisposition testing for BRCA1/2 does not pose major mental health risks, but our findings also show that the impact of prophylactic surgery on aspects such as body image and sexuality should not be underestimated, and that some women are at risk for high distress, and as a result, need more attentive care.

Hypospadias in sons of women exposed to diethylstilbestrol in utero : a cohort study

BACKGROUND Transgenerational effects of diethylstilbestrol (DES) have been reported in animals, but effects in human beings are unknown. Alerted by two case reports, we aimed to establish the risk of hypospadias in the sons of women who were exposed to DES in utero. METHODS We did a cohort study of all sons of a Dutch cohort of 16284 women with a diagnosis of fertility problems. We used a mailed questionnaire assessing late effects of fertility treatment to identify boys with hypospadias. We compared the prevalence rate of hypospadias between boys with and without maternal DES exposure in utero. FINDINGS 16284 mothers (response rate 67%) reported 8934 sons. The mothers of 205 boys reported DES exposure in utero. Four of these children were reported to have hypospadias. In the remaining 8729 children, only eight cases of hypospadias were reported (prevalence ratio 21.3 [95% CI 6.5-70.1]). All cases of hypospadias were medically confirmed. Maternal age or fertility treatment did not affect the risk of hypospadias. Children conceived after assisted reproductive techniques such as in-vitro fertilisation were not at increased risk of hypospadias compared with children conceived naturally (1.8, 0.6-5.7). INTERPRETATION Our findings suggest an increased risk of hypospadias in the sons of women exposed to DES in utero. Although the absolute risk of this anomaly is small, this transgenerational effect of DES warrants additional studies.

One Year Follow-Up of Women Opting for Presymptomatic Testing for BRCA1 and BRCA2: Emotional Impact of the Test Outcome and Decisions on Risk Management (Surveillance or Prophylactic Surgery)

Genetic testing enables women at risk for hereditary breast and/or ovarian cancer to find out whether they have inherited the gene mutation (BRCA1/BRCA2), and if so, to opt for frequent surveillance and/or prophylactic surgery (bilateral mastectomy and/or oophorectomy). Here, a follow-up is described for 63 healthy women at 50% risk of being a BRCA1/BRCA2 mutation carrier who underwent genetic testing. The course of distress and problems regarding body image and sexuality up to 1 year after disclosure of the test-outcome were described separately for mutation carriers undergoing mastectomy (n = 14), for mutation carriers opting for surveillance (n = 12) and for non-mutation carriers (n = 37). Furthermore, we analyzed whether women opting for prophylactic mastectomy differed from those opting for close surveillance with respect to biographical characteristics, experiences with cancer in relatives and personality. Women opting for prophylactic mastectomy had significantly higher distress levels than mutation carriers who opted for surveillance, and the non-mutation carriers. This difference in levels of distress was highest at pre- and post-test and had almost disappeared at 1-year follow-up. Besides, mutation carriers opting for prophylactic mastectomy were more often in their thirties, more often had young children and had a longer awareness of the genetic nature of cancer in the family than those opting for regular surveillance. Adverse effects were observed in women who underwent prophylactic mastectomy (mostly in combination with immediate breast reconstruction) regarding the perception of how their breast region looked like and felt, the intimate relationship and physical wellbeing whereas women opting for prophylactic mastectomy reported more distress than the other women in the study, their distress levels had significantly decreased 6 months or longer after surgery, possibly due to the significant risk reduction of developing breast cancer. This might explain, why most women who underwent prophylactic mastectomy were satisfied with this decision, despite a perceived negative impact on body image, the intimate relationship and physical wellbeing.

Optimum number of oocytes for a successful first IVF treatment cycle

Ovarian stimulation in IVF allows selection of embryos for transfer, but may have detrimental effects on oocyte and embryo quality and endometrial receptivity. This study investigated the optimal response to ovarian stimulation in terms of number of oocytes for achieving pregnancy in a first IVF cycle. Data from 7422 women who underwent their first IVF cycle for standard indications were analysed. All had been treated with exogenous gonadotrophins and gonadotrophin releasing hormone (GnRH) agonist co-treatment in a long down-regulation protocol between 1990 and 1995. Pregnancy rates in relation to the number of obtained oocytes were adjusted for age, fecundity, subfertility cause, gonadotrophin dosage, type of luteal support, and number of transferred embryos by multivariate analysis. Of the 7422 women who underwent oocyte retrieval, overall 85% had an embryo transfer and 24% conceived. The highest pregnancy rates per embryo transfer and per started cycle were observed when 13 oocytes were obtained (31 and 28%, respectively). This study supports the concept of an optimal range of oocytes obtained in response to ovarian stimulation for IVF, below and above which outcomes are compromised.

Use of Genetic Testing and Prophylactic Mastectomy and Oophorectomy in Women With Breast or Ovarian Cancer From Families With a BRCA1 or BRCA2 Mutation

PURPOSE To analyze the use of genetic testing, prophylactic mastectomy, and oophorectomy among women with breast and/or ovarian cancer from families with a BRCA1 or BRCA2 mutation. PATIENTS AND METHODS We examined prospectively the use of BRCA1/BRCA2 testing in all women with a primary breast or ovarian cancer from a consecutive series of 112 high-risk families in which a BRCA1/BRCA2 mutation eventually was identified. The rate of prophylactic bilateral and contralateral mastectomy and prophylactic oophorectomy was analyzed in the women who carried a BRCA1/BRCA2 mutation and who had no metastatic disease at the time of the genetic test disclosure. We examined predictors for genetic test uptake and prophylactic surgery using univariate and multivariate analysis. RESULTS Overall, 192 of 220 women (87%) with primary tumors underwent genetic testing. Eleven of these 192 tested women (6%) appeared not to carry the family-specific BRCA1/BRCA2 mutation. Genetic testing occurred significantly more frequently at ages younger than 50 years (P =.04) and in persons with multiple primary tumors (P =.02). Among eligible women, 35 of 101 (35%) requested bilateral or contralateral mastectomy, and 47 of 95 (49%) requested oophorectomy. Women aged younger than 50 years and women who developed their first tumor after the initial identification of a BRCA1/BRCA2 mutation in the family were significantly (both P =.01) more likely to opt for prophylactic bilateral or contralateral mastectomy. CONCLUSION In a clinical setting, we show a high demand for BRCA1/BRCA2 testing and for prophylactic surgery by women with breast and/or ovarian cancer from high-risk families.

The molecular genetics and morphometry‐based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system

The objective of this study was to compare the accuracy of disease progression prediction of the molecular genetics and morphometry‐based Endometrial Intraepithelial Neoplasia (EIN) and World Health Organization 1994 (WHO94) classification systems in patients with endometrial hyperplasias.

A low number of retrieved oocytes at in vitro fertilization treatment is predictive of early menopause

OBJECTIVE To investigate whether women with a low number of retrieved oocytes at the first in vitro fertilization (IVF) attempt have an increased risk of early menopause. DESIGN Nested case-control study. SETTING Twelve IVF clinics in the Netherlands. PATIENT(S) Women participating in a nationwide Dutch cohort study (OMEGA) of ovarian stimulation for IVF and subsequent gynecologic diseases (n = 26,428). Each patient who experienced natural menopause at or before 46 years (n = 38) was individually matched to five controls (n = 190) who had not yet entered menopause at the age the patient became postmenopausal. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Relative risk of reaching natural menopause at an early age (</=46 years), according to the number of retrieved oocytes at the first IVF attempt. RESULT(S) Women with a poor response (zero to three oocytes) had a relative risk of 11.6 (95% confidence interval: 3.9-34.7) of having an early menopause as compared with women who have a normal response (> three oocytes). Women who were stimulated with gonadotropins during IVF treatment but did not undergo an IVF puncture because of an anticipated poor response (canceled IVF cycle) had a relative risk of 8.3 (95% confidence interval: 2.9-23.9). CONCLUSION These results suggest that women with a low number of retrieved oocytes at the first IVF treatment are more likely to become postmenopausal at an early age than women with a higher number of retrieved oocytes. Our study is the first longitudinal study to provide strong evidence for the quantitative aspect of the ovarian concept of reproductive aging.

Cancer Risk Associated with Subfertility and Ovulation Induction: A Review

AbstractObjective: Over the past decades the use of fertility drugs (FDs) has greatly increased. Recently, the possible association between the use of FDs and risk of cancer has aroused great concern. In this paper, we critically review the available epidemiologic studies. Methods: We identified papers published between 1966 and 1999 that examined FDs and specific causes of subfertility in relation to the risks of cancers of the ovary, breast, endometrium and thyroid, and melanoma. Results: Although present insights into the pathogenesis of hormone-related malignancies suggest a possible association between the use of FDs and the risk of specific cancers, this has not been convincingly demonstrated in epidemiologic studies. With regard to cancer risk in relation to the cause of subfertility, the only consistent association observed is an increased risk of endometrial cancer for women with subfertility due to hormonal disorders. While positive findings in some studies on FDs and ovarian cancer risk have aroused serious concern, the associations observed in most of these reports appear to be due to bias or chance rather than being causal. The most important sources of bias are inadequate confounder control for both parity and causes of subfertility. Conclusions: To discriminate between the possible carcinogenic effects of various ovulation induction regimens, subfertility disorders, and reproductive characteristics associated with subfertility, future studies should include large populations of subfertile women with sufficient follow-up time. In such cohort studies the cause of subfertility should be measured adequately (based on medical records) and information about reproductive characteristics should be collected for all cohort members. Such studies should also include a group of subfertile women with an indication for FD use but not so treated.

No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study

BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3–10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7–2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5–3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers.

Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort

BACKGROUND Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown. METHODS We identified a nationwide historic cohort of 19 146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997–1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group. RESULTS After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16–2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62–6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25–14.33 and 2.14; 95% CI = 1.07–4.25, respectively, adjusted for age, parity and subfertility cause). CONCLUSIONS Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.