Environmental Effects On Fertility

National Institute Of Environmental Health Sciences

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Abstract

Data from the Early Pregnancy Study (EPS) (A.Wilcox, PI) provide a resource for ongoing research into reproductive hormones, fertility, & early pregnancy. During field work for this study in 1982-1985, women enrolled at the time they stopped using birth control in order to conceive. We followed them through their 8th week of pregnancy. They collected daily first morning urine specimens, and these were analyzed for human chorionic gonadotropin and steroid metabolites. Women with known fertility problems were excluded, so the sample represents normal unassisted reproduction. We conducted a pilot study to test the stability of hormones in urines stored from the Early Pregnancy Study. Pilot work supported the validity of BPA and phthalate measurements in the EPS urines after long-term storage. We designed a sample selection protocol (pool of 3 separate daily specimens) to the assess levels in each participant menstrual cycle and each clinical pregnancy. These have been analyzed at CDC. Analysis of these data indicate no increased risk of early pregnancy loss with phthalate or BPA exposure. We have extended the analyses to examine the relationship between these exposures and corpus luteum rescue, initial rise of human chorionic gonadotropin, corpus luteum rescue, and length of gestation. Several associations were found, but all will need replication before considered of clinical significance because our sample was small, and analyses did not account for multiple testing. Phenols in addition to PBA were also examined with indications of increased early pregnancy loss with higher 2,5-dichlorophenol concentrations, but increased fecundability with higher concentrations of butylparaben (OR: 1.62; 95% CI: 1.08, 2.44) and triclosan (OR: 1.49; 95% CI: 0.99, 2.26) Antimllerian hormone (AMH) is used as a biomarker for ovarian reserve which is measured in IVF clinics to assess the likelihood that a woman will produce enough eggs in a stimulation cycle to warrant IVF. It has been hypothesized to be a marker of fertility and has been used to crudely predict time of menopause among late-reproductive-age women. The majority of data on AMH come from fertility clinics and suggested that, with the exception of smoking, it is not perturbed by many of the normal factors associated with reproductive outcomes. We have been examining factors that might influence ovarian reserve as measured by AMH in several populations, including African Americans and Hispanics. Current use of oral contraceptives or Depo Provera are associated with lower AMH. Associations with BMI vary by population under study. Pregnancy and breastfeeding history are not associated with AMH in our general population sample. We continue to investigate the association between vitamin D (measured by the circulating biomarker for vitamin D status, 25-hydroxy vitamin D (25(OH)D) and reproductive characteristics including ovarian reserve. Women with high 25(OH)D have higher estrogen levels during the menstrual cycle, and in a separate sample, in several studies increased fecundability consistent with our suggestive findings of lower AMH. However, benefits to reproductive endpoints appear to depend on higher concentrations of 25(OH)D than are required for bone health. Early-life factors may have long-term effects on adult reproduction as classically demonstrated by studies of DES. We recently examined soy-formula as another estrogenic exposure of interest. Our finding support an association between soy formula feeding in infancy and elevated menstrual bleeding and pain as an adult. Additionally, if mom worked or lived on a farm during the pregnancy of interest the age-adjusted ovarian reserve was lower in the adult woman. The apparent adverse effects of prenatal farm exposures on ovarian reserve was replicated in a separate population. Perturbation in early development of the reproductive tract in infant girls may also have long-term adverse effects. We used data from the NIEHS Infant Feeding and Early Development Study to investigate early ovarian development. Ovarian growth and follicle development based on six ultrasound examinations conducted in this longitudinal study between birth and nine months. On average there is rapid ovarian growth for the first four months, with subsequent ultrasound examinations showing stable ovarian volumes or even slight decreases in volume. Antral follicles are common by the peak of growth at four months. Further analyses reveal that there are some female infants with very low ovarian activity during the first 9 months of life. This was supported by our analysis of AMH in these girls, with four separate groups emerging when analyzed with latent class analyses to identify clusters that whose AMH trajectories differed. One groups had generally low concentrations throughout. Adolescent and adult consequences for such female babies need to be assessed. As a collaborating researcher with the Apple Women's Health Study, the effect of COVID-19 vaccination on menstrual cycle characteristics were examined, with little indication of any major effects. Other research in this national cohort is ongoing. Additional research in progress is: 1) development of a method for identifying anovulatory cycles from basal body temperature data, so factors associated with anovulation can be studied in a general population for the first time and 2) assessment of subfertility in our cohort of young African-American women (both projects led by Dr. Anne Marie Jukic).