Transitions in pregnancy planning in women recruited for a large prospective cohort study.

STUDY QUESTION: Do the rates at which women transition among different intensities of pregnancy planning vary with age, marital status and race/ethnicity? SUMMARY ANSWER: Rates of transition from low or moderate pregnancy probability groups (PPGs) to higher PPGs vary by age, marital status and race/ethnicity. WHAT IS KNOWN ALREADY: The design of prospective studies of the effects of pre- and peri-conception exposures on fecundity, pregnancy and children's health is challenging because at any specific time only a small percentage of reproductive age women is attempting to conceive. To our knowledge, there has been no population-based, prospective study that repeatedly assessed pregnancy planning, which included women who were not already planning pregnancy at enrollment and whose ages spanned the female reproductive age range. STUDY DESIGN, SIZE, DURATION: A longitudinal study was carried out that repeatedly assessed pregnancy probability in 12 916 women for up to 21 months from January 2009 to September 2010. PARTICIPANTS/MATERIALS, SETTING, METHOD: We analyzed data from the National Children's Study Vanguard Study, a pilot study for a large-scale epidemiological birth cohort study of children and their parents. During the Vanguard Study, investigators followed population-based samples of reproductive age women in each of seven geographically dispersed and diverse study locations over time to identify when they sought to become pregnant, providing a unique opportunity to prospectively assess changes in pregnancy planning in a large sample of US women. At study entry and each follow-up contact, which occurred at 1, 3 or 6 month intervals depending on PPG, a questionnaire was used to assess behavior dimensions of pregnancy planning to assign women to low, moderate, high non-tryer and high tryer PPGs. MAIN RESULTS AND THE ROLE OF CHANCE: Crude rates of pregnancy increased with higher assigned PPG, validating the utility of the instrument. The initial PPG and probabilities of transitioning from low or moderate PPG to higher PPG or pregnancy varied with age, marital status and race/ethnicity. Women aged 25 to <35 years had shorter times to transition to higher PPGs or to pregnant compared with women <25 years. Women who were not currently married had longer times to transition from any initial PPG to pregnant, high tryer or high non-tryer status than currently married women. Non-Hispanic Black (NHB) and Hispanic women had shorter time to transition from low or moderate to high non-tryer than non-Hispanic White (NHW) women. NHB women also had shorter time to transition from low to high tryer than NHW women. High tryers are more likely to be aged 25 to <30 years, to be married, and to be Hispanic, NHB or other race/ethnicity than women in the low PPG. LIMITATIONS, REASONS FOR CAUTION: Loss to follow-up varied by age, marital status and race/ethnicity. Although weights were not developed for the Vanguard study, the self-weighting design minimizes the bias of unweighted analysis. Nonetheless, the SEs for some estimates may be under-estimated. WIDER IMPLICATIONS OF THE FINDINGS: Our results show that demographic characteristics are strong predictors of women's behaviors toward pregnancy. The results further show that frequent follow-up assessments of pregnancy planning behavior in large numbers of women are required to recruit an unbiased sample of preconception women. These findings will be useful to investigators designing prospective studies of fecundability, pregnancy outcomes and children's health. STUDY FUNDING/COMPETING INTERESTS: National Institutes of Health (contracts N01-HD53414, N01-HD63416, N01-HD53410, N01-HD53415, N01-HD53396, N01-HD53413 and N01-HD-53411; grant R21 ES016846) and by the University of California Irvine Center for Occupational and Environmental Health. No competing interests. TRIAL REGISTRATION NUMBER: None.

Temporal association between serum prolactin concentration and exposure to styrene.

BACKGROUND: Previous studies have suggested that occupational exposure to styrene is associated with increased serum levels of the anterior pituitary hormone prolactin (PRL). AIMS: To test the hypotheses that: (1) the effect of styrene exposure on PRL secretion is an acute effect, not a subchronic or chronic effect; (2) blood styrene, as a measure of absorbed dose, is a stronger predictor of serum PRL level than personal breathing zone air styrene concentration. METHODS: Subjects were recruited from 17 workplaces in the reinforced plastics industry. Personal breathing zone air styrene, whole blood styrene, and serum PRL were measured during one to three sessions, approximately one year apart. Linear multiple regression was used to model the relations between acute (air styrene or blood styrene obtained at same time as PRL), subchronic (average air or blood styrene over two or three sessions), and chronic (years of work in industry or facility times average air styrene over all sessions) indices of styrene exposure and serum PRL. RESULTS: Acute blood styrene concentration was the strongest predictor of serum PRL concentration, with the model predicting a 2.06-fold increase in PRL (95% CI 1.11 to 3.84) for every 10-fold increase in blood styrene. Serum PRL tended to increase with increasing styrene exposure in both men and women; however, women tended to have higher PRL levels. For women, the change in blood styrene between sessions 1 and 2 was a significant predictor of the change in serum PRL between sessions. CONCLUSIONS: Results confirm that styrene exposure enhances serum PRL concentrations and support an acute effect of styrene on PRL secretion.

Gonadotropin regulation of glutathione synthesis in the rat ovary.

Glutathione (GSH), an antioxidant and conjugator of electrophilic toxicants, prevents toxicant-mediated destruction of ovarian follicles and oocytes. Ovarian GSH has previously been shown to change with estrous cycle stage in rats, suggesting that the gonadotropin hormones may regulate ovarian GSH synthesis. The present studies tested the hypotheses that [1] estrous cycle-related changes in ovarian GSH result from cyclic changes in protein and mRNA expression of the rate-limiting enzyme in GSH synthesis, glutamate cysteine ligase (GCL, also called gamma-glutamylcysteine synthetase), and [2] that these changes result from gonadotropin-mediated regulation of GCL subunit expression. In the first experiment, ovaries were harvested from cycling adult female rats on each stage of the estrous cycle. In the second experiment immature female rats were injected with pregnant mare's serum gonadotropin (PMSG) to stimulate follicular development or with vehicle and killed 8, 24, or 48 h later. In both experiments the ovaries were harvested for [1] total GSH assay, [2] Western analysis for GCL catalytic (GCLc) and regulatory (GCLm) subunit protein levels, or [3] Northern analysis for Gclc and Gclm mRNA levels. Ovarian GSH concentrations and Gclc and Gclm mRNA levels, but not GCL subunit protein levels, varied significantly with estrous cycle stage. PMSG administration significantly increased ovarian GSH concentrations 24 and 48 h later. GCLm protein levels increased significantly at 24 h and 48 h following PMSG. GCLc protein levels did not increase significantly following PMSG. Gcl subunit mRNA levels were not significantly increased at any time point by the planned ANOVA; however, an increase in Gelc at 48 h was identified by t-testing. These results support the hypothesis that gonadotropins regulate ovarian GSH synthesis by modulating GCL subunit expression.

Calls on reproductive and developmental toxicants to a regional poison center.

We sought to characterize calls received by a regional Poison Center concerning reproductive hazards and to assess the quality of the responses. Data was extracted for a 3 mo period from all calls regarding reproductive or in utero developmental effects. The Poison Center responses were evaluated based on completeness of information gathered and final recommendations made. Two hundred seventy-one calls regarding 335 products were received. Ninety-seven percent of the calls concerned exposures during a pregnancy. Fifty-nine percent of the substances of concern were drugs; 32% were other chemicals; 7% were biological agents. Eleven percent of the exposures were occupational; 22% were environmental. Thirty-four percent of the exposures had not yet occurred. Sixty-two percent were characterized as no or minimal risk. For 13% of exposures, callers were advised to avoid initiating or continuing the exposure. Callers were referred to physicians or specialty services for 11% of exposures. The majority of responses were felt to be appropriate. Problematic areas included inconsistent advice and lack of referral. Discussion of exposures in light of other risk factors for and background rates of adverse reproductive outcomes, as well as more frequent referral to a specialist with expertise in reproductive toxicology was recommended.

Reproductive endocrine effects of acute exposure to toluene in men and women.

OBJECTIVES: Despite observation of adverse reproductive effects of toluene, including alterations of serum gonadotropins (luteinising hormone (LH) and follicle stimulating hormone (FSH)) in humans, little is known of the mechanism of toxicity. The hypothesis was tested that toluene acutely suppresses pulsatile gonadotropin secretion by measuring LH and FSH at frequent intervals during controlled exposure to toluene. METHODS: Women in the follicular and luteal phases of the menstrual cycle and men were randomised to inhale filtered air with or without 50 ppm toluene through a mouthpiece for 3 hours (19% of the OSHA permissible exposure limit). Blood was sampled by intravenous catheter at 20 minute intervals for 3 hours before, 3 hours during, and 3 hours after exposure. Plasma LH, FSH, and testosterone were measured. Pulse amplitude, pulse frequency, and mean concentrations of LH and FSH for each of the 3 hour periods before, during and after exposure to toluene versus sham exposure were calculated with the ULTRA pulse detection program and compared by analysis of variance (ANOVA) with repeated measures. RESULTS: In men mean concentrations of LH showed a significant interaction (p < 0.05) between exposure and sampling period, with a greater LH decline during exposure to toluene than sham exposure. However, there was no concomitant effect on testosterone concentrations. The LH pulse frequency of women in the luteal phase showed a trend towards a significant interaction between exposure and sampling period (p = 0.06), with a greater decline in pulse frequency during exposure to toluene than sham exposure. There were no other significant effects of exposure to toluene. CONCLUSIONS: Three hour exposure to 50 ppm toluene did not result in abnormal episodic LH or FSH secretion profiles, however, subtle effects on LH secretion in men and women in the luteal phase were found. The clinical relevance of these effects is unclear, indicating the need for further study of reproductive function in exposed workers.

Acute changes in pulsatile LH and FSH secretion after ovariectomy in rats: treatment with oestradiol for 24 h suppresses LH, but not FSH, for at least 48 h.

Concentrations of LH in female rats do not increase to concentrations seen in the male at 24 h after castration until up to one week after ovariectomy, while FSH concentrations increase rapidly in both sexes. We hypothesized that the lag in LH rise is due to the imposition of a prolonged suppression by the high concentrations of oestradiol seen during each cycle at pro-oestrus, which prevents a rapid response to the removal of negative feedback. This hypothesis was tested by studying the effect of exposure to pro-oestrus oestradiol concentrations, administered in Silastic capsules, for 24 h on the pulsatile release of LH and FSH. In the first experiment, treatment with oestradiol for 24 h began on day 3 after ovariectomy and resulted in a significant suppression of LH pulse frequency, which appeared to persist for up to 4 days after removal of the implant. In the second experiment, exposure for 24 h to high, pro-oestrous oestradiol concentrations beginning on day 3 or 7 after ovariectomy significantly suppressed mean LH concentrations and LH pulse amplitude compared with vehicle-treated controls, while FSH secretion did not differ between the two treatments. These results suggest that the acute lag in the rate of LH rise after ovariectomy depends on a prolonged suppressive effect of oestradiol and that the rise in oestradiol during the cycle, which exerts a positive feedback to trigger the preovulatory gonadotrophin surges, also exerts a negative feedback for 3-4 days, and this contributes to the relative stability of cycle duration in female rats.

Differential gonadotropin responses to N-methyl-D,L-aspartate in metestrous, proestrous, and ovariectomized rats.

Peripheral administration of N-methyl-D,L-aspartate (NMA), an analogue of the excitatory amino acid aspartate, elicits LH and prolactin (PRL) release in rats, most likely by increasing endogenous releasing-hormone secretion. These experiments were carried out to assess the degree to which NMA stimulates FSH and to analyze the relationship between endocrine status and responsiveness to NMA in female rats, in contrast to male rats, as described in the companion paper [Biol Reprod 48:000-000]. In experiment 1, estrous rats (n = 10) and diestrous rats (n = 10) and in experiment 2, estrous rats (n = 11) and rats ovariectomized (OVX) 8 days previously (n = 10) were fitted with atrial catheters and injected s.c. with 100 micrograms of an LHRH antagonist or vehicle at 2100 h. Starting at 0900 h the next day (metestrus, proestrus, or Day 9 post-OVX), blood was withdrawn every 10 min for 3 h. Each animal received i.v. 5 mg NMA after the first hour and i.v. 500 ng LHRH after the second hour. NMA significantly increased LH in metestrous and proestrous females, and LHRH antagonist blunted the increases. In OVX females, LH decreased after NMA. FSH was not affected by NMA in any group. PRL increased after NMA in proestrous and metestrous animals. LHRH caused surge-like LH and small FSH increases in vehicle groups; these increases did not differ in amplitude between intact and OVX animals and were blunted by pretreatment with LHRH antagonist. In experiment 3, 10 diestrous rats were fitted with atrial catheters and were serially bled at 2-h intervals from 1200 h on the following day (proestrus) until 0600 h on estrus morning. After the first sample the animals were injected s.c. with 0.2 mg/kg MK801, a noncompetitive NMA receptor antagonist, or with saline. Four of the 5 saline-treated animals exhibited surges of LH and FSH as well as elevated progesterone levels, with LH and progesterone peaking at 2000 h. Five of 5 MK801-treated animals failed to have elevated LH, FSH, or progesterone levels at any time point. These data demonstrate that LHRH mediates the LH response to NMA in rats and that endogenous NMA receptor binding may be necessary for the preovulatory gonadotropin surges. The lack of FSH responses to NMA during periods of low-level gonadotropin secretion suggests that physiological increments in endogenous LHRH secretion sufficient to induce a pulse of LH are insufficient to stimulate pulse-like FSH release.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential gonadotropin responses to N-methyl-D,L-aspartate in intact and castrated male rats.

Peripheral administration of N-methyl-D,L-aspartate (NMA), a neuroexcitatory amino acid agonist, probably stimulates LH release through an increase in endogenous LHRH secretion. In the present study, NMA and a potent LHRH antagonist were used to determine the degree to which release of FSH is similarly dependent upon the acute secretion of LHRH. A second aim was to compare responsiveness of LHRH neurons to NMA in castrated and intact male rats. Adult male rats were castrated (n = 10) or sham castrated (n = 11) on the morning of Day 0. After 8 days, rats were fitted with atrial catheters between 0900 and 1200 h; at 2100 h they received s.c. either oil vehicle or 100 micrograms of an LHRH antagonist. Starting at 0900 h on Day 9, 0.5-ml blood samples were collected every 10 min for 3 h. After 1 h of sampling each animal received i.v. 5 mg of NMA in 0.5 ml 0.9% saline. An hour later each rat received i.v. 500 ng of LHRH in 0.5 ml saline. Plasma LH, FSH, and prolactin (PRL) levels were determined by RIA. In the oil-treated sham castrates, mean plasma LH levels were increased by 110% (p < 0.01) within 10 min and remained elevated for 30 min after the injection of NMA. The profile of this LH secretory response was similar to or slightly more robust than endogenous LH pulses observed previously. The NMA-induced LH release was completely blocked by pretreatment with LHRH antagonist. In both oil- and antagonist-treated sham-castrated rats, NMA administration failed to elicit a concomitant increase in plasma FSH levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex differences in acute luteinizing hormone responses to gonadectomy remain after progesterone antagonist and dopamine agonist treatment.

In male rats, LH pulse frequency and amplitude increase dramatically by 24 h after gonadectomy; in females they increase only slightly by this time. Mean FSH levels increase significantly in both sexes by 24 h after gonadectomy. The objectives of the present studies were to compare pulsatile LH, FSH, and prolactin (PRL) secretion in intact versus gonadectomized and in male versus female rats, and to determine whether the acute postovariectomy lag in LH rise is due to a lingering effect of the higher PRL and/or progesterone (P) levels seen in intact females. LH pulse amplitude, frequency, and mean levels increased significantly by 24 h after gonadectomy in both sexes, but the increases were greater in the males. FSH mean levels, but not pulse amplitude or frequency, increased similarly in both sexes by 24 h after gonadectomy. PRL did not change with gonadectomy. Treatment with CB-154 (a dopamine agonist), with or without RU486 (a P antagonist), 1 h before gonadectomy significantly suppressed pulsatile PRL secretion 1 day later in both sexes. There was no effect of either treatment on LH secretion. We have demonstrated that there is a sex difference in LH, but not FSH or PRL, pulsatility at 24 h after gonadectomy, and that female rats' higher PRL and P levels do not account for their slow rate of LH rise after ovariectomy.