Variability in the practice of fertility preservation for patients with cancer

Fertility is important to women and men with cancer. While options for fertility preservation (FP) are available, knowledge regarding the medical application of FP is lacking. Therefore we examined FP practices for cancer patients among reproductive endocrinologists (REs). A 36 item survey was sent to board-certified REs. 98% of respondents reported counseling women with cancer about FP options. Oocyte and embryo cryopreservation were universally offered by these providers, but variability was noted in reported management of these cases-particularly for women with breast cancer. 86% of the respondents reported using letrozole during controlled ovarian stimulation (COS) in patients with estrogen receptor positive (ER+) breast cancer to minimize patient exposure to estrogen. 49% of respondents who reported using letrozole in COS for patients with ER+ breast cancer reported that they would also use letrozole in COS for women with ER negative breast cancer. Variability was also noted in the management of FP for men with cancer. 83% of participants reported counseling men about sperm banking with 22% recommending against banking for men previously exposed to chemotherapy. Overall, 79% of respondents reported knowledge of American Society for Clinical Oncology FP guidelines-knowledge that was associated with providers offering gonadal tissue cryopreservation (RR 1.82, 95% CI 1.14-2.90). These findings demonstrate that RE management of FP in cancer patients varies. Although some variability may be dictated by local resources, standardization of FP practices and communication with treating oncologists may help ensure consistent recommendations and outcomes for patients seeking FP

High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects.

Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment.We examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage.Our results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes

Persistent organic pollutants and early menopause in U.S. women.

Endocrine-disrupting chemicals (EDCs) adversely affect human health. Our objective was to determine the association of EDC exposure with earlier age of menopause.Cross-sectional survey using National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2008 (n = 31,575 females). Eligible participants included: menopausal women >30 years of age; not currently pregnant, breastfeeding, using hormonal contraception; no history of bilateral oophorectomy or hysterectomy. Exposures, defined by serum lipid and urine creatinine-adjusted measures of EDCs, data were analyzed: > 90th percentile of the EDC distribution among all women, log-transformed EDC level, and decile of EDC level. Multi linear regression models considered complex survey design characteristics and adjusted for age, race/ethnicity, smoking, body mass index. EDCs were stratified into long (>1 year), short, and unknown half-lives; principle analyses were performed on those with long half-lives as well as phthalates, known reproductive toxicants. Secondary analysis determined whether the odds of being menopausal increased with EDC exposure among women aged 45-55 years.This analysis examined 111 EDCs and focused on known reproductive toxicants or chemicals with half-lives >1 year. Women with high levels of β-hexachlorocyclohexane, mirex, p,p'-DDE, 1,2,3,4,6,7,8-heptachlorodibenzofuran, mono-(2-ethyl-5-hydroxyhexyl) and mono-(2-ethyl-5-oxohexyl) phthalate, polychlorinated biphenyl congeners -70, -99, -105, -118, -138, -153, -156, -170, and -183 had mean ages of menopause 1.9 to 3.8 years earlier than women with lower levels of these chemicals. EDC-exposed women were up to 6 times more likely to be menopausal than non-exposed women.This study of a representative sample of US women documents an association between EDCs and earlier age at menopause. We identified 15 EDCs that warrant closer evaluation because of their persistence and potential detrimental effects on ovarian function. Earlier menopause can alter the quantity and quality of a woman's life and has profound implications for fertility, human reproduction, and our global society

Evaluating groups of endocrine disrupting chemicals and their potential impact on female reproduction.

<p>Evaluating groups of endocrine disrupting chemicals and their potential impact on female reproduction.</p

Standard and experimental options utilizing ART for FP in cancer patients [1,9,10].

<p>Standard and experimental options utilizing ART for FP in cancer patients [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127335#pone.0127335.ref001" target="_blank">1</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127335#pone.0127335.ref009" target="_blank">9</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127335#pone.0127335.ref010" target="_blank">10</a>].</p

Oocyte MII spindles and chromosome alignment defects.

<p>[A] The MII oocytes from control mice display a typical barrel shaped spindle and organized chromosomes on the metaphase plate. Oocytes from HFD mice [B] revealed abnormal fragmented appearing spindles and clustered chromosomes. [C] Quantitative analysis revealed both spindle defects [45.3% vs 13.2%, *p = 0.0008] and chromosome misalignment [35.8% vs 17.5%, **p = 0.04] were increased in HFD fed mice compared to control mice. N = 146 control oocytes from 7 mice and n = 138 HFD oocytes from 7 mice were analyzed. Data are expressed as mean percentage ± SD from three independent experiments.</p

Embryos from HFD mice experience a higher frequency of degradation and delayed developmental progression.

<p>[A] Representative image of embryos collected from control and HFD mice at 46 h post-hCG. Red and black arrowheads indicate degraded and 1-cell embryos, respectively. Scale bar, 100 µm. [B] Quantification of 1-cell, 2-cell and degraded embryos from control and HFD mice [n = 110 control embryos from 6 mice and n = 184 HFD embryos from 9 mice, pooled from three replicates]. [C] Histogram showing the blastocyst formation rate of 2-cell embryos from control and HFD mice. [n = 90 for control and n = 65 for HFD pooled from three replicates]. Error bars indicate ± sd. *, P<0.05 vs. control.</p

Fetal and placenta size and brain abnormalities.

<p>[A] Embryos from mothers on a high fat diet were significantly smaller than those from a control diet [12.1 mm vs 13.2 mm; *p<0.001]. Similarly, placentas from the HFD mothers were significantly smaller than placentas originating from control blastocysts [7.9 mm vs 8.9 mm; *p<0.001]. [B] d14.5 fetuses from HFD [left] and Control [right]; example shown for HFD illustrates the more extreme end of the spectrum of growth retarded fetuses. [C] H & E staining of control fetus and fetal brain vs HFD fetus and HFD fetal brain. All fetuses were from transferred blastocysts. Abnormal development of both the ventricles and the choroid plexus is seen in 40% of the HFD blastocyst-derived fetuses. Scale bars, 500 µm.</p

Oocyte and Cumulus cell mitochondrial ultrastructure.

<p>Oocyte mitochondria from HFD [A] and Control [B] mice. [C] Histogram shows that oocytes from HFD have higher rates of abnormal mitochondrial morphology. Cumulus cell mitochondria from HFD [D] and control [E] mice. [F] Histogram demonstrating that cumulus cells from HFD have higher rates of abnormal mitochondrial morphology. Arrows indicate the vacuoles in mitochondria.</p

Standard COS protocols and timing in menstrual cycle.

<p>Events depicted above the grid occur in natural menstrual cycles whereas events depicted below the grid depict timing of administration of medications for COS protocols. Color in the grid is representative of rising estradiol levels during the menstrual cycle and COS protocols.</p