Adverse effects on reproductive capacity can occur at every phase of the reproductive process from prenatal development, puberty, to time when conception is occurring and the pregnancy is developing. This research project includes several aspects of the reproductive process, but mostly focuses on factors affecting the ability to conceive and maintain the pregnancy through its first few weeks. The complex biological processes involved include gamete development and maturation, sperm transport through the female reproductive tract, fertilization, early development of the conceptus, implantation, and maintenance of the developing embryo/trophoblast. We have developed methods to estimate environmental effects on fecundability, defined as the per menstrual cycle probability of conceiving, and we have followed women with daily urinary hormone measurements through their pregnancy attempts and early pregnancies. The biological underpinnings of fertility can also influence general health, and we have considered the health effects of female hormones within the framework of this project? ? 1.Data from the Early Pregnancy Study (A.Wilcox, PI) provide a resource for ongoing research into reproductive hormones, fertility, & early pregnancy. This study enrolled women at the time they stopped using birth control in order to conceive & followed them through their 8th week of pregnancy. They collected daily first morning urine specimens & these were analyzed for human chorionic gonadotropin & estrogen and progesterone metabolites. Women with known fertility problems were excluded, so the sample represents normal unassisted reproduction. We have completed analyses of follicular phase length in the Early Pregnancy Study data, & we find longer follicular phases among women who reported using marijuana. This is biologically plausible given the research showing effects on LH secretion & ovulation. We are also examining variation in menstrual bleeding. Pregnancies lost within 6 weeks of last menstrual period are followed by bleeding that on average varies little from normal menses. However, among those early pregnancies, the associatied bleeding increases with length of the pregnancy. The shortest pregnancies actually have bleeding which is less than seen for normal menses. This raises questions about endometrial function in these pregnancies. We conducted a pilot study to test the stability of hormones in urines stored from the Early Pregnancy Study. We collected a sample of new daily urine specimens during early pregnancy to serve as a reference to evaluate the quality of the stored samples. Estrogen and progesterone metabolite as well as hCG measurements from a sample of the stored urines will be compared to these hormones measured in newly collected urine samples. We enrolled 44 women, 26 of whom became pregnant and collected daily first morning urine specimens. Urine samples from the new collection and stored EPS samples are being analyzed for estrogen and progesterone metabolites as well as for hCG by Jim Kesner at NIOSH.? 2.A subsample of urine specimens from the EPS have also been analyzed for phthalates, bisphenol A, and cortisol to see if those analytes can be evaluated in these stored samples. If so, we will analyze specimens from the complete sample in order to examine the relationship between these exposures and fertility and early pregnancy. ? 3. Data that allow for estimation of fecundability & the factors that affect it can be as simple as self-reported time to pregnancy data or as detailed as daily monitoring of sexual intercourse in relation to time of ovulation during a menstrual cycle. There is methodologic interest is quality of self-reported time-to-pregnancy data, and there have been several efforts to evaluate the validity of such reports. Data comparing prospectively collected data & retrospective reporting indicate that females can report time to pregnancy relatively well, even several years after the reference pregnancy. To better evaluate accuracy of male report we compared male with female report of time to pregnancy. Then we examined the quality of male-reported confounder data for time to pregnancy studies (partner's use of oral contraceptive as last method before pregnancy and her smoking habits), and found those to be reported reasonably well. Other important self-reported data in reproductive studies involve menstrual cycle characteristics. We are evaluating the validity of self-reported cycle characteristics by comparing interview data to prospective daily recording of menstrual bleeding & pelvic pain. In another methodologic project, we are using available data to determine how well women can report the timing of their positive pregnancy test. Bias arises in spontaneous abortion & time-to-pregnancy studies when comparing exposed and unexposed groups that differ in timing of pregnancy testing. Those who tend to have delayed pregnancy testing will recognize fewer spontaneous abortions, & they will have longer times to pregnancy. ? 4. Using data from the Agricultural Health Study, we found that men with high BMI are more likely to be infertile than men of normal weight for height. We replicated those findings in a Norwegian population where data were also were collected on frequency of intercourse. With these additional data we demonstrated that the lower fertility among men with higher BMI does not appear to be explained by them having less sex.
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