Sirpa Mäkinen

A Role for the Androgen Receptor in Follicular Atresia of Estrogen Receptor Beta Knockout Mouse Ovary

Abstract Estrogen receptor beta (ERβ) is highly expressed, but ERα is not detectable in granulosa cells in the mouse ovary. In ERβ knockout (BERKO) mice, there is abnormal follicular development and very reduced fertility. At 3 wk of age, no significant morphologic differences were discernable between wild type (WT) and BERKO mouse ovaries, but by 5 mo of age, atretic follicles were abundant in BERKO mice and there were very few healthy late antral follicles or corpora lutea. At 2 yr of age, unlike the ovaries of their WT littermates, BERKO mouse ovaries were devoid of healthy follicles but had numerous large, foamy lipid-filled stromal cells. The late antral and atretic follicles in BERKO mice were characterized by a high level of expression of the androgen receptor (AR) and IGF-1 receptor. These proteins were abundantly expressed in granulosa cells of preantral and early antral follicles in both genotypes, but their expression was extinguished in late antral follicles of WT mice. Healthy late antral follicles and corpora lutea were restored in BERKO ovaries after 15 days of treatment of mice with the antiandrogen flutamide. The results suggest that in the absence of ERβ there was a loss of regulation of AR. Because androgens enhance recruitment of primordial follicles into the growth pool and cause atresia of late antral follicles, the inappropriately high level of AR probably is related to the follicular atresia and to the early exhaustion of follicles in BERKO mice.

Does long in vitro culture promote large for gestational age babies

STUDY QUESTION Does the length of time during which embryos are cultured in vitro affect the birthweight of the infants? SUMMARY ANSWER The duration of the embryo culture period is a significant factor in determining the birthweight of the infants. WHAT IS ALREADY KNOWN IVF children show adverse perinatal outcome when compared with the general population and increased incidence of preterm birth and low birthweight is commonly observed. STUDY DESIGN, SIZE, DURATION A retrospective cross-sectional cohort study including 1079 infants born after treatment at the Family Federation of Finland Fertility Clinic in Helsinki, between 2000 and 2010. PARTICIPANTS, SETTING, METHODS All singleton IVF children were included. The gestation- and gender-adjusted birthweights of the babies were analyzed according to mothers age, BMI, and parity, type of treatment (IVF or ICSI), main cause of infertility and embryo culture period. Two outcomes were investigated: the birthweight and the proportion of small and large for gestational age (SGA and LGA) infants. Multiple linear regression analysis was performed to show the significance of each individual factor on determining the birthweight of the babies born. MAIN RESULTS AND THE ROLE OF CHANCE In the study group as a whole, the distribution of the SGA and LGA babies showed no deviation from the growth charts of the general population. However, when the birthweight of the children was analyzed according to the length of embryo culture from Day 2 to Days 5-6, an increase in the proportion of LGA babies was found (D2 9.4%, D3 11.5%, D5-6 18.8%; D2 n = 871, D3 n = 139, D5-6 n = 69). Multiple linear regression analysis showed that BMI (P < 0.001) and parity (P < 0.001) of the mother, as well as the embryo culture period (P = 0.007) had a significant effect on the birthweight. The value of the adjusted R(2) was 0.437. LIMITATIONS, REASONS FOR CAUTION Small number of D5-6 infants and a lack of pregnancy-associated factors contributing to birthweight. WIDER IMPLICATIONS OF THE FINDING This study warrants larger studies to analyze the birthweight of the IVF children, particularly after blastocyst culture. STUDY FUNDING/COMPETING INTEREST The study was funded by the Family Federation of Finland, Fertility Clinic Helsinki. No competing interests.

Bone marrow remission status predicts leukemia contamination in ovarian biopsies collected for fertility preservation.

Bone marrow remission status predicts leukemia contamination in ovarian biopsies collected for fertility preservation

Effect of Previous Chemotherapy on the Quality of Cryopreserved Human Ovarian Tissue In Vitro

Background Cryopreservation of ovarian tissue has been widely accepted as an option for fertility preservation among cancer patients. Some patients are exposed to chemotherapy prior to ovarian tissue cryopreservation. Consequently, assessment of the developmental capacity of human ovarian tissue after chemotherapy is of primary importance. Materials In order to study the impact of previous chemotherapy on in vitro development and viability of ovarian follicles, quality control samples from 34 female cancer patients at median age of 15 years (range 1‒35), cryopreserved for fertility preservation before (n = 14) or after (n = 20) initiation of chemotherapy, were thawed and cultured for 7 days. The morphology and developmental stages of ovarian follicles were studied by light microscopy before and after culture. Possible associations between follicular densities, age and exposure to alkylating agents, expressed as cyclophosphamide equivalent dose (CED) were tested. Results Exposure to chemotherapy significantly impaired the survival and development of ovarian follicles in culture. After seven days, significantly higher densities of intermediary, primary and secondary follicles and lower densities of atretic follicles was detected in the samples collected before chemotherapy. Increasing dose of alkylating agents was identified by multivariate linear regression analysis as an independent predictor of a higher density of atretic follicles, whereas increasing age of the patient predicted a better outcome with less follicle atresia and a higher density of maturing follicles. Conclusion This study provides quantitative in vitro evidence of the impact of chemotherapy on developmental capacity of cryopreserved human ovarian tissue. The results indicate that fertility preservation should be carried out, if possible, before initiation of alkylating agents in order to guarantee better in vitro survival of ovarian follicles. In addition, ovarian samples from younger girls show lower viability and fewer developing follicles in culture.