Is cortisol excretion independent of menstrual cycle day? A longitudinal evaluation of first morning urinary specimens.

BACKGROUND: Cortisol is frequently used as a marker of physiologic stress levels. Using cortisol for that purpose, however, requires a thorough understanding of its normal longitudinal variability. The current understanding of longitudinal variability of basal cortisol secretion in women is very limited. It is often assumed, for example, that basal cortisol profiles do not vary across the menstrual cycle. This is a critical assumption: if cortisol were to follow a time dependent pattern during the menstrual cycle, then ignoring this cyclic variation could lead to erroneous imputation of physiologic stress. Yet, the assumption that basal cortisol levels are stable across the menstrual cycle rests on partial and contradictory evidence. Here we conduct a thorough test of that assumption using data collected for up to a year from 25 women living in rural Guatemala. METHODOLOGY: We apply a linear mixed model to describe longitudinal first morning urinary cortisol profiles, accounting for differences in both mean and standard deviation of cortisol among women. To that aim we evaluate the fit of two alternative models. The first model assumes that cortisol does not vary with menstrual cycle day. The second assumes that cortisol mean varies across the menstrual cycle. Menstrual cycles are aligned on ovulation day (day 0). Follicular days are assigned negative numbers and luteal days positive numbers. When we compared Models 1 and 2 restricting our analysis to days between -14 (follicular) and day 14 (luteal) then day of the menstrual cycle did not emerge as a predictor of urinary cortisol levels (p-value>0.05). Yet, when we extended our analyses beyond that central 28-day-period then day of the menstrual cycle become a statistically significant predictor of cortisol levels. SIGNIFICANCE: The observed trend suggests that studies including cycling women should account for day dependent variation in cortisol in cycles with long follicular and luteal phases.

Interpretation of intraoperative parathyroid hormone monitoring in patients with baseline parathyroid hormone levels of <100 pg/mL.

BACKGROUND: Common guidelines for intraoperative parathyroid hormone (IOPTH) interpretation are based on clearly elevated baseline parathyroid hormone (PTH) values. We hypothesize that patients with low-baseline levels (<100 pg/mL) have a higher incidence of multigland disease (MGD) and display differences in PTH kinetics compared with patients with high-baseline levels. METHODS: We retrospectively reviewed the cases of 1151 patients with primary hyperparathyroidism who underwent parathyroidectomy with IOPTH monitoring. Of these, 141 patients had low-baseline values. Multiple comparisons were made between the low-baseline and high-baseline groups. RESULTS: Twenty-six percent of the low-baseline patients had MGD versus 15% of the high-baseline patients (P = .002). The PTH kinetics differed between groups after gland excision at both 5 and 10 minutes. Adherence solely to the "50% rule" during minimally invasive parathyroidectomy potentially would have missed 25% of patients with MGD in the low-baseline group versus 10% in the high-baseline group; 5.7% of the low-baseline patients had persistent or recurrent hypercalcemia versus 2.9% of the high-baseline patients. CONCLUSION: MGD is significantly more prevalent among low-baseline patients, and PTH kinetics are somewhat different between groups. The current guidelines that are used for IOPTH monitoring may not be ideal for use in this low-baseline group and will likely need to be revised after further study of this group of patients.

Cortisol levels and very early pregnancy loss in humans.

Maternal stress is commonly cited as an important risk factor for spontaneous abortion. For humans, however, there is little physiological evidence linking miscarriage to stress. This lack of evidence may be attributable to a paucity of research on maternal stress during the earliest gestational stages. Most human studies have focused on "clinical" pregnancy (>6 weeks after the last menstrual period). The majority of miscarriages, however, occur earlier, within the first 3 weeks after conception (approximately 5 weeks after the last menstrual period). Studies focused on clinical pregnancy thus miss the most critical period for pregnancy continuance. We examined the association between miscarriage and levels of maternal urinary cortisol during the first 3 weeks after conception. Pregnancies characterized by increased maternal cortisol during this period (within participant analyses) were more likely to result in spontaneous abortion (P < 0.05). This evidence links increased levels in this stress marker with a higher risk of early pregnancy loss in humans.

Stress and female reproductive function: a study of daily variations in cortisol, gonadotrophins, and gonadal steroids in a rural Mayan population.

We report here on a longitudinal study of stress and women's reproduction in a small Kaqchikel Mayan community in rural Guatemala. Current understanding of the effects of stress on the reproductive axis in women is mostly derived from clinical studies of individual stressors. Little is known, however, about the cumulative effects of "real life" stress. Cortisol increases in response to a broad variety of individual stressors (Tilbrook et al., 2002). In this article, we evaluate the association between daily fluctuations in women's urinary cortisol and reproductive hormones: estrone conjugates (E(1)C), pregnandiol glucuronide (PdG), luteinizing hormone (LH), and follicle stimulating hormone (FSH). To assess the association between daily changes in cortisol levels and changes in the profiles of the reproductive hormones, we used a random coefficients model based on polynomial regression. The sample includes 92 menstrual cycles provided by 24 participants over a year-long prospective study. Increases in urinary cortisol levels were associated with significant increases in gonadotrophin and progestin levels during the follicular phase. Also, in a time window between days 4 and 10 after ovulation, increased cortisol levels were associated with significantly lower progestin levels. These results are significant because untimely increases in gonadotrophins and low midluteal progesterone levels have previously been reported to impinge on the ovulatory and luteinization processes and to reduce the chances of successful implantation (Ferin, 1999; Baird et al., 1999). Future research should consider the possibility that stress may affect fecundability and implantation without necessarily causing amenorrhoea or oligomenorrhoea.

An alternative analysis of intraoperative parathyroid hormone data may improve the ability to detect multiglandular disease.

HYPOTHESIS: A nomogram based on regression analysis of intraoperative parathyroid hormone level decay discriminates single gland disease from multiglandular (MG) disease more accurately than the currently used 50% rule. DESIGN: Retrospective case series. SETTING: Academic health center. PATIENTS: Two hundred thirty-five patients (222 patients with single gland disease and 13 patients with MG disease) who underwent parathyroidectomy. INTERVENTIONS: Intraoperative parathyroid hormone level analysis at baseline, time 1 (about 5 minutes), and time 2 (about 10 minutes) after excision of the first gland. MAIN OUTCOME MEASURES: The mean slope was calculated at time 1 and time 2 and analyzed using one-way analysis of variance and the Fisher least significance difference post hoc tests using data normalized to baseline intraoperative parathyroid hormone levels to compare patients with single gland disease with patients with MG disease. A regression-based nomogram was created to analyze individual kinetic decay data. RESULTS: The mean (SEM) single gland disease slope was significantly steeper than the MG disease slope at both time 1 (-0.91 [0.02] vs -0.66 [0.05]; P<.01) and time 2 (-0.77 [0.01] vs -0.56 [0.05]; P<.01). When the standard threshold rule of a 50% decrease from baseline was used, only 23% of the patients with MG disease were correctly predicted by intraoperative parathyroid hormone values (77% false-positive result rate) at time 1. However, the nomogram correctly predicted 54% of the patients with MG disease at time 1 (46% false-positive result rate). At time 2, the standard threshold 50%-rule method correctly predicted 38% of the patients with MG disease (62% false-positive result rate), while the nomogram still correctly classified 54% of the patients with MG disease (46% false-positive result rate). CONCLUSIONS: A regression-based nomogram incrementally improves prediction of MG disease compared with the standard 50%-rule method and accounts for variability in the exact timing of samples. Slope analysis suggests that the earliest time point best isolates the kinetics of the excised gland. The nomogram will need to be validated prospectively.

The influence of sample site on intraoperative PTH monitoring during parathyroidectomy.

BACKGROUND: Intraoperative parathyroid hormone (IOPTH) monitoring is common during parathyroidectomy. We hypothesized that sample site (peripheral vs central vein) may impact IOPTH interpretation. METHODS: Two hundred and one patients underwent curative parathyroidectomy for single-gland disease. IOPTH was drawn peripherally (PV) in 114 patients and centrally (CV, jugular vein) in 87 patients. Decrease from baseline IOPTH and the presence of a normal value at 10 and 15 minutes were determined. The slope of IOPTH decay was calculated. These data were compared between sample sites. RESULTS: Median baseline IOPTH was 268 pg/mL (CV) and 191 pg/mL (PV, P = .003). The mean IOPTH decay slopes were -0.75 (PV) and -0.76 (CV, P = NS), and the mean percent IOPTH decrease at 10 minutes was 79% PV and 80% CV (P = NS). At 10 minutes, a > or =50% drop from baseline was seen in 94% (CV) versus 97% (PV) of patients ( P = NS), resulting in a median IOPTH of 40 pg/mL (CV) versus 34 pg/mL (PV, P = .09). By 15 minutes, the central IOPTH had decreased by > or =50% of baseline in 98% of patients ( P = NS when compared to the 10-minute PV site). CONCLUSIONS: IOPTH kinetics are largely the same for PV and CV sample sites, but baseline values are higher with central sampling. Consequently, CV IOPTH levels are generally higher at 10 minutes, but this discrepancy resolves by 15 minutes. The surgeon utilizing CV samples may need to extend the sampling period.

Hybridization studies of cultured human pituitary prl and gh producing adenoma cells: Effects of thyrotropin-releasing hormone, somatostatin, and phorbol ester.

The effects of the hypothalamic hormones, thyrotropin-releasing hormone (TRH), and somatostatin (SRIH), and of phorbol 12-myristate 13-acetate (PMA) on PRL and GH secretion and messenger RNA (mRNA) levels were analyzed in 10 GH and/or PRL producing adenomas after culturing the tumor cells in the presence of these secretagogues for 7 days. The expression of chromogranin A and B mRNAs was also examined. All four of the clinically diagnosed GH adenomas expressed or secreted both GH and PRL while four of six clinically diagnosed prolactinomas produced or secreted both PRL and GH. Prolactinomas had less than 10% of tumor cells expressing chromogranin A mRNA while more than 40% of the adenoma cells expressed chromogranin B mRNA. TRH stimulated PRL secretion and increased PRL mRNA levels while SRIH decreased GH secretion and mRNA expression in some cases. Unexpectedly, PMA stimulated PRL mRNA levels four- to sevenfold above control levels in two adenomas and generally stimulated chromogranin A and B mRNA expression but not GH mRNA, as determined by Northern hybridization and in situ hybridization analyses.These results indicate that cultured prolactinoma cells express significantly more chromogranin B mRNA than chromogranin A mRNA, and that PMA increases PRL mRNA expression in some prolactinomas, although the effect of PMA on various adenomas reflects the heterogeneity of these tumors with respect to protein kinase C stimulation.