For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

BACKGROUND Semen quality is taken as a surrogate measure of male fecundity in clinical andrology, male fertility, reproductive toxicology, epidemiology and pregnancy risk assessments. Reference intervals for values of semen parameters from a fertile population could provide data from which prognosis of fertility or diagnosis of infertility can be extrapolated. METHODS Semen samples from over 4500 men in 14 countries on four continents were obtained from retrospective and prospective analyses on fertile men, men of unknown fertility status and men selected as normozoospermic. Men whose partners had a time-to-pregnancy (TTP) of < or =12 months were chosen as individuals to provide reference distributions for semen parameters. Distributions were also generated for a population assumed to represent the general population. RESULTS The following one-sided lower reference limits, the fifth centiles (with 95th percent confidence intervals), were generated from men whose partners had TTP < or = 12 months: semen volume, 1.5 ml (1.4-1.7); total sperm number, 39 million per ejaculate (33-46); sperm concentration, 15 million per ml (12-16); vitality, 58% live (55-63); progressive motility, 32% (31-34); total (progressive + non-progressive) motility, 40% (38-42); morphologically normal forms, 4.0% (3.0-4.0). Semen quality of the reference population was superior to that of the men from the general population and normozoospermic men. CONCLUSIONS The data represent sound reference distributions of semen characteristics of fertile men in a number of countries. They provide an appropriate tool in conjunction with clinical data to evaluate a patient's semen quality and prospects for fertility.

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World Health Organization reference values for human semen characteristics

WHO laboratory manual for the examination and processing of human semen

https://apps.who.int/iris/bitstream/10665/78102/1/WHO_HSE_PHE_IHE_2013.1_eng.pdf

State of the Science of Endocrine Disrupting Chemicals - 2012

BACKGROUND Reported declines in sperm counts remain controversial today and recent trends are unknown. A definitive meta-analysis is critical given the predictive value of sperm count for fertility, morbidity and mortality. OBJECTIVE AND RATIONALE To provide a systematic review and meta-regression analysis of recent trends in sperm counts as measured by sperm concentration (SC) and total sperm count (TSC), and their modification by fertility and geographic group. SEARCH METHODS PubMed/MEDLINE and EMBASE were searched for English language studies of human SC published in 1981-2013. Following a predefined protocol 7518 abstracts were screened and 2510 full articles reporting primary data on SC were reviewed. A total of 244 estimates of SC and TSC from 185 studies of 42 935 men who provided semen samples in 1973-2011 were extracted for meta-regression analysis, as well as information on years of sample collection and covariates [fertility group ('Unselected by fertility' versus 'Fertile'), geographic group ('Western', including North America, Europe Australia and New Zealand versus 'Other', including South America, Asia and Africa), age, ejaculation abstinence time, semen collection method, method of measuring SC and semen volume, exclusion criteria and indicators of completeness of covariate data]. The slopes of SC and TSC were estimated as functions of sample collection year using both simple linear regression and weighted meta-regression models and the latter were adjusted for pre-determined covariates and modification by fertility and geographic group. Assumptions were examined using multiple sensitivity analyses and nonlinear models. OUTCOMES SC declined significantly between 1973 and 2011 (slope in unadjusted simple regression models -0.70 million/ml/year; 95% CI: -0.72 to -0.69; P < 0.001; slope in adjusted meta-regression models = -0.64; -1.06 to -0.22; P = 0.003). The slopes in the meta-regression model were modified by fertility (P for interaction = 0.064) and geographic group (P for interaction = 0.027). There was a significant decline in SC between 1973 and 2011 among Unselected Western (-1.38; -2.02 to -0.74; P < 0.001) and among Fertile Western (-0.68; -1.31 to -0.05; P = 0.033), while no significant trends were seen among Unselected Other and Fertile Other. Among Unselected Western studies, the mean SC declined, on average, 1.4% per year with an overall decline of 52.4% between 1973 and 2011. Trends for TSC and SC were similar, with a steep decline among Unselected Western (-5.33 million/year, -7.56 to -3.11; P < 0.001), corresponding to an average decline in mean TSC of 1.6% per year and overall decline of 59.3%. Results changed minimally in multiple sensitivity analyses, and there was no statistical support for the use of a nonlinear model. In a model restricted to data post-1995, the slope both for SC and TSC among Unselected Western was similar to that for the entire period (-2.06 million/ml, -3.38 to -0.74; P = 0.004 and -8.12 million, -13.73 to -2.51, P = 0.006, respectively). WIDER IMPLICATIONS This comprehensive meta-regression analysis reports a significant decline in sperm counts (as measured by SC and TSC) between 1973 and 2011, driven by a 50-60% decline among men unselected by fertility from North America, Europe, Australia and New Zealand. Because of the significant public health implications of these results, research on the causes of this continuing decline is urgently needed.

Temporal trends in sperm count: a systematic review and meta-regression analysis.

Is serum progesterone(P) level on day 2 of vaginal P administration in a hormonally substituted mock cycle predictive of live birth in oocyte donation(OD)? Retrospective analysis of 110 mock cycles from 2008 to 2016 of OD recipients having at least one subsequent embryo transfer (ET). Endometrial preparation consisted of sequential administration of vaginal estradiol, followed by transdermal estradiol and 600 mg/day vaginal micronized P. In mock cycles, serum P was measured 2 days after vaginal P introduction. OD was performed 1 to 3 years later, without P measurement. In mock cycles, mean serum P level on day 2 was 12.8 ± 4.5 ng/mL (range: 4–28 ng/mL). A total of 32% patients had P < 10 ng/mL. At the time of first OD, age of recipients and donors, number of retrieved and attributed oocytes, and number of transferred embryos were comparable between patients with P < 10 ng/mL in their mock cycles compared with P ≥ 10 ng/mL. Pregnancy and live birth rate after first ET were significantly lower for patients with P < 10ng/mL (9% vs. 35 %; P = 0.002 and 9% vs. 32%; P = 0.008, respectively). Considering both fresh and subsequent frozen-thawed ET, cumulative live birth rate per-patient and per-transfer were significantly lower in patients with P < 10 ng/mL in their mock cycle (14% vs. 35%; P = 0.02 and 11% vs. 27%; P = 0.03). A low P level in hormonally substituted cycles several years before ET performed with the same endometrial preparation is associated with a significantly lower chance of live birth. This suggests that altered vaginal P absorption is a permanent phenomenon. Monitoring serum P in hormonally substituted cycles appears mandatory to adjust luteal P substitution.

Women utilizing oocyte donation have a decreased live birth rate if they displayed a low progesterone level in a previous hormonal replacement mock cycle

Disease-free survival does not differ according to fertility preservation technique for young women with breast cancer.

Health effects of Bisphenol A

of the experiment. The counting chamber was left for 10–15 min and counting was then performed using positive phase-contrast optics with a magnification of ×400, according to the instructions provided by the WHO.1 In light of the absence of a state of the art definition in spermiology, our results were compared with data from the literature (when available) and with the criteria defined by the biological variations calculated on within-subject and between-subject biologic variation (Ricos).3 All of the determinations of concentrations were done blinded by four different operators on 60 sperm samples (concentrations ranging from 0.4 × 106 ml−1 to 382.5 × 106 ml−1). Differences in Bland–Altman plots4 showed concordance of sperm concentration values measured with the Kova and the Neubauer devices (Figure 1a). Three points of discrepancy were above the 95% limit of agreement, without any clinical impact given the high values. The correlation between the two methods was studied with Tessier’s least rectangle regression, by fitting a linear equation to the observed data. Statistical correlation revealed a coefficient of determination R2 = 0.982 (Figure 1b), indicating correct linearity of the regression and thus a strong association between the values determined with the Kova and the Neubauer devices.5 Differences in accuracy,5 evaluated for four levels of selected clinical interest (5 × 106 ml−1, 30 × 106 ml−1, 100 × 106 ml−1, and 300 × 106 ml−1), were 13.8%, 1.9%, 4.1%, and 4.7%, respectively. The mean relative difference between both of the methods was 3.6%, with a 95% confidence interval that ranged from 1.7% to 8.9%. All of these values were lower than the limit of inaccuracy B (15.6%).3 The statistical power of comparison between both methods, calculated with a threshold of 10% and a risk of 5%, was 99.5%, assuming that there is no statistical difference between both methods for sperm concentration measurement. Repeatability was expressed as the coefficient of variation (CV). Each sample was counted ten times for each calibrated bead and five times for each semen sample by the same operator. The CVs were 9.2% and 5.7% for level 1 and level 2 bead solutions, respectively. They were 8.6% and 7.9% for the low (20 × 106 ml−1) and high (200 × 106 ml−1) sperm level samples, respectively. All of the CVs were lower than the reported intratechnician CV, which averaged 12.5% for hemocytometer counts,6 and they were similar to that reported for technicians with daily practice (9.8%).7 Reproducibility was expressed as the CV. To our knowledge, there is no consensus in regard to the method to obtain reproducibility. Dear Editor, In its latest edition, the World Health Organization (WHO) provides guidelines regarding the standardization of techniques for the measurement of sperm concentration1 and recommends use of a 100 μm-deep hemocytometer. However, these instructions are not always followed correctly.2 Furthermore, although hemocytometers provide more accurate and consistent results, they present several drawbacks: the chamber must be properly assembled prior to its use so as to ensure that the counts are correct and it needs to be cleaned thoroughly to remove all traces of sperm, which risks breaking the glass coverslip. A disposable counting chamber (Kova) exhibits several advantages: low cost, ease of use (e.g., no cleaning, no need for mounting the coverslip, and a fixed device); disposability, which is particularly advantageous with sperm infected with virus; and the possibility of processing 10 samples. Here, we sought to validate the Kova chamber as a reliable device for the measurement of sperm concentration, according to the ISO 15189 standards. Samples consisted of latex beads (Qwik Check®, Theradiag, Marne-la-Vallée, France) and semen samples from infertile patients collected by masturbation in the laboratory, after having provided informed consent (Bichat Hospital, APHP, Paris, France). Two levels of latex beads were used: level 1 ((22 ± 5.5) × 106 beads ml−1) and level 2 ((46 ± 11.5) × 106 beads ml−1). After the samples were mixed, they were diluted using positive-displacement pipettes in a 0.35% (v/v) formalin solution (dilutions ranged from 1:2 to 1:100). A 10 μl diluted aliquot of either latex beads or patient sperm sample was then loaded in a counting chamber (Kova® Glasstic® Slide 10 [CML, Nemours, France] and/or an improved Neubauer chamber [Dutscher, Brumath, France]) depending on the nature LETTER TO THE EDITOR

Florence Eustache

Papers

Women utilizing oocyte donation have a decreased live birth rate if they displayed a low progesterone level in a previous hormonal replacement mock cycle

Disease-free survival does not differ according to fertility preservation technique for young women with breast cancer.

Health effects of Bisphenol A

Sperm concentration measurement with a disposable counting chamber.

Bisphenol A at low doses: Updated evidence on reproductive function