应激生物标志物可预测生育力骤降

明尼阿波利斯——在儿科与围产期流行病学研究学会(SPPER)年会上报告的一项以配偶为基础的前瞻性研究显示，应激生物标记物α淀粉酶(而非皮质醇)水平升高与受孕机会降低有密切关联。

尽管大量证据提示应激对妊娠结局具有负面影响，但关于应激与受孕关联的经验性数据却出奇得少。一项包含13例女性的澳大利亚小型前瞻性研究显示，受孕和未受孕周期的尿液肾上腺素、去甲肾上腺素或皮质醇浓度无统计学差异(Hum. Reprod. 1997;12:2324-9)。Lynch博士及其同事近期发表的一项对339例年龄18~40岁的试图受孕女性的研究，也未发现自我报告的应激、焦虑和抑郁与妊娠之间存在关联(Fertil. Steril. 2012 June 13 [epub ahead of print])。

“我们之前曾发表在英国类似人群中的结果，这两项研究结果惊人的相似，”Lynch博士说。在英国研究中(Fertil. Steril. 2011;95:2184-9)，经校正配偶年龄、受孕时间窗内的性交频率以及女性饮酒情况后，发现α淀粉酶与第1个试孕周期内的生育能力呈负相关(OR，0.85)。妊娠几率随受孕时间窗内每天皮质醇水平的四分位增高而上升，而随α淀粉酶水平四分位的增高而降低。生育能力风险率的相反方向的证据支持：与α淀粉酶相关的生育能力降低是通过交感神经系统而非下丘脑-垂体-肾上腺轴介导的。

Courtney D. Lynch博士

第一作者Courtney D. Lynch博士表示，这是首次在美国对试图受孕者前瞻性评估生理性应激与生育能力。作为LIFE研究(对生育能力和环境的纵向研究)的一部分，当前的分析是基于密西根州和德克萨斯州501对希望要孩子的配偶，对其随访最长达12个月，如发生妊娠，则在妊娠期间继续随访。在入组的次日和研究中第1次月经开始的次日，收集女性唾液样本，使用酶联免疫吸附法测定皮质醇和α淀粉酶浓度。入组女性的年龄为18~40岁，多数为白人(78%)、有高等学历(75%)、不吸烟(73%)。受试者平均年龄为30岁，其中53%未生育，55%超重或肥胖。

结果显示，在完成方案的401对配偶中，87%成功妊娠，13%未成功妊娠。数据完整可评估的393对配偶的结果显示，成功妊娠和未成功妊娠女性的皮质醇(分别为0.46 μg/dl 和0.36 μg/dl)或α淀粉酶水平(23.6 U/ml和32.0 U/ml)无统计学差异，俄亥俄州立大学的流行病学家Lynch博士说。唾液皮质醇处于最低三分位(0.02~0.30 μg/dl；OR，1.0)、中间三分位(0.31~0.42 μg/dl；OR，0.90)或最高三分位(0.43~15.60 μg/dl；OR，0.91)女性的经校正妊娠风险率相似。但与α淀粉酶处于最低三分位(0.4~10.4 U/ml；OR，1.0)的女性相比，α淀粉酶处于中间(10.5~23.6 U/ml；OR，0.89)和最高三分位(23.7~379.0 U/ml；OR，0.69)的女性的经校正妊娠风险率显著降低。考虑到相关协变量的影响。研究者还使用了Bayesian统计学技术确定受孕时间窗并估计每日受孕几率。基于这项分析，在其他协变量为平均水平的情况下，1名α淀粉酶处于最低、中间和最高三分位的30岁白人女性与比其年长2岁的配偶，在受孕时间窗第1天成功妊娠的几率分别为26%、24%和20%。

研究者总结认为，唾液中的α淀粉酶作为一种新的应激生物标志物，可预测生育能力的变化。

Lynch博士及其同事披露无相关利益冲突。

爱思唯尔  版权所有

By: PATRICE WENDLING, Clinical Endocrinology News Digital Network

MINNEAPOLIS – Increased levels of the stress biomarker alpha-amylase, but not cortisol, are significantly associated with a lower chance of conception, a couple-based, prospective study has shown.

The odds of pregnancy were slashed 31% for women whose salivary levels of alpha-amylase were in the highest tertile, compared with women whose levels were in the lowest tertile after adjustment for such important confounders as the difference between partners’ ages, intercourse during the fertile window and the woman’s age, income, race, parity, smoking, caffeine intake, and alcohol use (odds ratio, 0.69).
 
This study is the first in the United States to prospectively examine the association between physiologic stress and fecundity among couples trying to conceive, lead author Courtney D. Lynch, Ph.D., said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

"We previously published similar results in a population in the U.K., and we were quite astounded that we found exactly the same thing," she said.

In that study (Fertil. Steril. 2011;95:2184-9), alpha-amylase was negatively associated with fecundity in the first cycle of attempting pregnancy (OR, 0.85) after adjustment for the couples’ age, intercourse frequency during the fertile window, and female alcohol use.

The current analysis was based on 501 couples in Michigan and Texas who were attempting pregnancy and were followed for up to 12 months and then through pregnancy, if pregnancy occurred, as part of the LIFE (Longitudinal Investigation of Fertility and the Environment) study. Cortisol and alpha-amylase concentrations were determined by enzyme immunoassay from salivary samples collected by the women on the day following enrollment and the day following the start of their first menses in the study.

The women, aged 18-40 years, were mostly white (78%), college graduates (75%), and nonsmokers (73%). Their mean age was 30 years, 53% were nulliparous, and 55% were overweight or obese.

Of the 401 couples who completed the protocol, 87% achieved pregnancy and 13% did not.

Complete data evaluable on 393 couples showed no significant differences between women who did or did not become pregnant in mean levels of cortisol (0.46 μg/dL vs. 0.36 μg/dL) or alpha-amylase (23.6 U/mL vs. 32.0 U/mL), said Dr. Lynch, an epidemiologist at Ohio State University in Columbus.

The adjusted odds of pregnancy were similar for women with salivary cortisol in the lowest tertile (0.02-0.30 μg/dL; OR, 1.0), middle tertile (0.31-0.42 μg/dL; OR, 0.90), or highest tertile (0.43-15.60 μg/dL; OR, 0.91).

The adjusted odds of pregnancy were significantly diminished, however, for women with alpha-amylase levels in the middle (10.5-23.6 U/mL; OR, 0.89) or highest tertile (23.7-379.0 U/mL; OR, 0.69), compared with the lowest tertile (0.4-10.4 U/mL; OR, 1.0), she said.

The investigators also used Bayesian statistical techniques to identify the fertile window and estimate day-specific probabilities of conception, taking into account the relevant covariates. Based on this analysis, the probability of pregnancy on day 1 of the fertility window for a 30-year-old, nonsmoking white woman with a partner 2 years older than she and all other covariates centered at the mean, was 26% for women in the lowest alpha-amylase tertile, 24% in the middle tertile, and 20% in the highest tertile, Dr. Lynch said.

The results of a similar analysis in the U.K. cohort showed that conception probabilities increased with increasing quartiles of cortisol for each day during the fertile window, but that the opposite was true for alpha-amylase, as increasing quartiles reduced all day-specific probabilities of conception. The opposing direction of fecundity odds ratios provides evidence that the reduction in fecundity associated with alpha-amylase was mediated via the sympathetic nervous system rather than through the hypothalamic-pituitary-adrenal axis, Dr. Lynch said.

Although the U.S. analysis could not assess the effect of stress over time with only two salivary samples, the data lend further support to the existence and directionality of the stress and fecundity association, she said.

Despite a plethora of evidence that stress negatively impacts pregnancy outcomes, empiric data on stress and conception are surprisingly sparse. A small prospective Australian study involving 13 women found no significant difference in urinary epinephrine, norepinephrine, or cortisol concentrations between conception and nonconception cycles (Hum. Reprod. 1997;12:2324-9).

A newly published study by Dr. Lynch and her colleagues also found no association between self-reported stress, anxiety and depression, and pregnancy after several confounders were controlled for in 339 women, aged 18-40, attempting to conceive (Fertil. Steril. 2012 June 13 [epub ahead of print]).

When asked by the audience how her two studies could come to such different conclusions, Dr. Lynch replied that "when you ask people if they are stressed, if people are chronically stressed they’re not going to perceive this day as any worse than another day in their situation, but that doesn’t mean the body doesn’t respond."

Indeed, the U.K. investigators concluded that alpha-amylase, the principal salivary protein secreted from the parotid gland, may be a "novel biomarker for assessing psychosocial stressors and reproductive end points, as mediated via the sympathetic nervous system." They pointed out that because alpha-amylase is produced locally in the oral cavity, it remains in relatively high concentrations compared with other salivary markers such as cortisol that is released elsewhere in the body by the adrenal gland and transported to the saliva via ultrafiltration.

Dr. Lynch and her colleagues reported no relevant financial disclosures.