In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse

Bisphenol A (BPA) is a known reproductive toxicant in rodents. However, the effects of in utero BPA exposure on early ovarian development and the consequences of such exposure on female reproduction in later reproductive life are unclear. Thus, we determined the effects of in utero BPA exposure during a critical developmental window on germ cell nest breakdown, a process required for establishment of the finite primordial follicle pool, and on female reproduction. Pregnant FVB mice (F0) were orally dosed daily with tocopherol-striped corn oil (vehicle), diethylstilbestrol (DES; 0.05 μg/kg, positive control), or BPA (0.5, 20, and 50 μg/kg) from gestational day 11 until birth. Ovarian morphology and gene expression profiles then were examined in F1 female offspring on postnatal day (PND) 4 and estrous cyclicity was examined daily after weaning for 30 days. F1 females were also subjected to breeding studies with untreated males at three to nine months. The results indicate that BPA inhibits germ cell nest breakdown via altering expression of selected apoptotic factors. BPA also significantly advances the age of first estrus, shortens the time that the females remain in estrus, and increases the time that the females remain in metestrus and diestrus compared to controls. Further, F1 females exposed to low doses of BPA exhibit various fertility problems and have a significantly higher percentage of dead pups compared to controls. These results indicate that in utero exposure to low doses of BPA during a critical ovarian developmental window interferes with early ovarian development and reduces fertility with age.     

The Desire for Children and Fertility Issues Among Young German Cancer Survivors

PurposeFor young cancer patients, family planning is not always completed at the time of cancer diagnosis. This study investigated young cancer patients' desire to have children, its intensity, and their discussion with oncologists and fertility specialists about fertility. Furthermore, gender differences, differences between childless patients and patients with children, and correlations with psychological distress were analyzed.MethodsA total of 149 cancer patients (range, 18–45 years of age) answered a self-developed questionnaire. Psychological distress was measured with the Patient Health Questionnaire.ResultsSeventy-four percent of patients had a desire to have children at the time of diagnosis. Whereas the intensity of the desire for children increased pre- to post-treatment in childless patients, it decreased in patients who already had children. A total of 55 patients who wanted a child (50%) needed supportive care concerning this issue; 60% of the total sample had discussed fertility aspects with their oncologists and 20% with fertility specialists. Patients reported higher levels of satisfaction with their discussions with fertility specialists than with their discussions with oncologists. Men (56%) underwent fertility preservation more often than did women (31%). Female sex was the only variable predicting psychological distress, whereas parenthood, fertility preservation, and desire for children had no significant impact.ConclusionsThe desire to have children and the fertility issues involved are important for young cancer patients. Reasons for not discussing fertility aspects with oncologists and the cause of low referral rates to fertility specialists should be explored in future studies. The implementation of structured psychosocial supportive care might address the needs of highly fertility-distressed patients.     

Predictors of ovarian malignancy in children: Overcoming clinical barriers of ovarian preservation

Background/Purpose

Ovarian preservation is desirable in girls with benign ovarian masses. We aimed to 1) identify clinical predictors of malignant ovarian masses, 2) investigate how often ovarian tissue is present to preserve in benign masses, and 3) identify factors associated with successful ovarian preservation.

Methods

Retrospective analysis (1997–2012) of girls age 1–18 years with an ovarian mass managed operatively. Data on presenting symptoms, imaging, biochemical markers, treatment, outcome, and pathology were extracted.

Results

We identified 150 patients. Large mass size, solid components, and elevated tumor markers (AFP, βHCG, and/or LDH) were significantly predictive of malignancy. All masses < 10 cm, predominantly cystic, and with negative tumor markers were benign. Masses with all three of these characteristics would decrease a 20% malignancy pretest probability to a posttest probability of 0.25%. Benign masses managed by oophorectomy contained normal ovarian tissue in 76% of the specimens. For benign masses, successful ovarian preservation was significantly associated with size < 10 cm, predominantly cystic, laparoscopy, and absence of torsion or calcifications.

Conclusion

Ovarian masses that are < 10 cm, primarily cystic, and have negative tumor markers are most likely benign. Viable ovarian tissue is frequently present in benign masses, so significant efforts should be made for ovarian preservation.     

Scientific principles of regenerative medicine and their application in the female reproductive system

The goal of regenerative medicine is to repair, replace, or regenerate diseased tissues/organs in order to restore normal function. In this paper we will first discuss the general principle of regenerative medicine and the various techniques and approaches that have been used to replace or regenerate cells in diseased tissues and organs. Then, we will review different regenerative medicine approaches that have been used to treat specific diseased tissues and organs of the reproductive system in both animal and human experiments. It is clear from this article that regenerative medicine holds significant promise, and we hope that the review will serve as a platform for further development of regenerative medicine technologies for the treatment of inadequacies of the reproductive system.     

Coenzyme Q supports distinct developmental processes in Caenorhabditis elegans

Coenzyme Q (Q) regulates aging in Caenorhabditis elegans, and its deficiency leads to a variety of pathologies in humans. We used a coq-8 deleted strain to study the role of Q in C. elegans development and how it influences life span. Endogenous Q₉ content of coq-8(ok840) knockouts was demonstrated to be about 7% of that found in the wild-type, indicating the basal biosynthesis rate is reduced in this strain. Knockouts abnormally developed both gonads and hypodermis, showed reduced fertility and shortened life span, and this was partially recovered by ingestion of exogenous Q. Knockouts produced embryos that showed arrested development at the time of initial expression of coq-8 in embryo. Uridine, whose biosynthesis depends on mitochondrial Q, improved both egg production and progeny under Q-rich dietary conditions. COQ-8 is a candidate protein for post-translational regulation of Q biosynthesis rate and its expression correlates with Q content during the life cycle in C. elegans. We show for the first time that a critical level of Q is necessary to support embryo development and fertility in C. elegans. These results suggest that extra-mitochondrial function of Q is a key factor linking development and bioenergetics in C. elegans.     

Anti-Müllerian Hormone in Female Adolescent Cancer Patients Before,During, and After Completion of Therapy: A Pilot Feasibility Study

Study ObjectiveAlkylating agents are implicated in premature ovarian insufficiency. To optimize counseling regarding future ovarian function in survivors of adolescent cancer, we describe anti-Müllerian hormone (AMH) levels in female adolescents at diagnosis, during, and shortly after completion of chemotherapy.Design, Setting, Participants, Interventions, and Main Outcome MeasuresThis was a prospective single-institution study. Participants were a mixed population of newly diagnosed postmenarchal female adolescents with malignancy. AMH was performed at diagnosis (T1), 6 months from diagnosis (T2), at end of therapy or 12 months [T3, whichever came first], 1 year after the end of therapy or 24 months from diagnosis [T4, whichever came first], and 18 months from the time of diagnosis (T5). All patients had baseline pelvic ultrasound examinations. Presence of menses and hot flashes were recorded at each time point.ResultsSixteen participants with a median age at diagnosis of 14.3 years (range 12-17 years) were followed for 18.2 months (range, 14-24 months). Oncology diagnoses included leukemia, lymphoma, and sarcoma. Ten patients (62.5%) received alkylating agents with a median cumulative dose of 3041 mg/m² (range, 2639-6478 mg/m²) of cyclophosphamide. Almost half (n = 7; 44%) experienced amenorrhea during treatment with resumption of menses in 6 of 7 patients (85%). Fifteen of 16 (94%) participants showed a decline in mean AMH levels by 6 months (T2) from diagnosis (15.8 IU/mL at T1 vs 6.5 IU/mL at T2; P = .003) and 12 of 15 (80%) showed at least some recovery of AMH (mean AMH at T4 = 13.2 IU/mL compared with 6.5 IU/mL at T2; P = .02). There was no difference in the mean decline nor recovery of AMH in those who did, vs did not receive cyclophosphamide.ConclusionTo our knowledge, this is the largest series to date in adolescents showing that AMH is uniformly suppressed during cancer therapy and short-term recovery occurs in just more than half of the patients by 18-24 months. The contribution of short-term AMH measurements in predicting long-term ovarian function remains to be defined. Long-term follow-up with serial AMH levels is required to help predict those at risk for premature ovarian insufficiency.     

Effect of infertility on quality of life of women: a validation study of the Turkish FertiQoL

The fertility quality of life (FertiQoL) measure specifically evaluates the impact of fertility problems in various life areas. The aim of this study was to examine the relationship between FertiQoL and the hospital anxiety and depression scale (HADS) in the Turkish population. All female patients who underwent various fertility treatments in our infertility clinic from May 2011 to May 2014 were approached to participate in the study and 389 completed the questionnaires. Our results showed that the four core scales of the FertiQoL measure had a Cronbach’s α value that was between 0.70 and 0.89. Two scales (anxiety and depression) of HADS both had a Cronbach’s α value of 0.80. These values present a reliable usage of FertiQoL and HADS measures (α?>?0.60). Significant negative correlations were found between the FertiQoL scales and HADS scales, ranging from ?0.27 (between relational scale of FertiQoL and anxiety scale of HADS) to ?0.65 (between mind–body scale of FertiQoL and depression scale of HADS). The results of this study provide supportive data to confirm that the Turkish version of FertiQol can accurately evaluate QoL in women who seek fertility treatment in Turkey.     

Can We Keep the ‘PROMISE’? AGO Breast Commission: Commentary on Recent Evidence Regarding LHRH Analogues for the Preservation of Ovarian Function

Recently reported data from the German ZORO trial and the Italian PROMISE-GIM6 trial have come to different conclusions. The AGO Breast Commission does not recommend the general use of luteinizing hormone-releasing hormone (LHRH) analogues for the preservation of ovarian function. Instead, we distinguish between patients with hormone receptor-negative and hormone receptor-positive disease. This article reviews the AGO recommendations in light of the ZORO and PROMISE-GIM6 data. In conclusion, separate recommendations are needed for the prevention of ovarian failure and for fertility preservation because the trials did not investigate fertility rate as a primary outcome measure. The results from not yet published trials such as OPTION and POEM may shed new light on the role of LHRH analogues.