A survival analysis approach to modeling human fecundity

Understanding conception probabilities is important not only for helping couples to achieve pregnancy but also in identifying acute or chronic reproductive toxicants that affect the highly timed and interrelated processes underlying hormonal profiles, ovulation, libido, and conception during menstrual cycles. Currently, 2 statistical approaches are available for estimating conception probabilities depending upon the research question and extent of data collection during the menstrual cycle: a survival approach when interested in modeling time-to-pregnancy (TTP) in relation to women or couples' purported exposure(s), or a hierarchical Bayesian approach when one is interested in modeling day-specific conception probabilities during the estimated fertile window. We propose a biologically valid discrete survival model that unifies the above 2 approaches while relaxing some assumptions that may not be consistent with human reproduction or behavior. This approach combines both the survival and the hierarchical models allowing investigators to obtain the distribution of TTP and day-specific probabilities during the fertile window in a single model. Our model allows for the consideration of covariate effects at both the cycle and the daily level while accounting for daily variation in conception. We conduct extensive simulations and utilize the New York State Angler Prospective Pregnancy Cohort Study to illustrate our approach. We also provide the code to implement the model in R software in the supplemental section of the supplementary material available at Biostatistics online.     

Studies of fertility and fecundity: comparative approaches from demography and epidemiology

The approaches used by demographers and by epidemiologists for studying the fecundity of couples (i.e. their ability to conceive) have converged, whereas they were historically divergent. Demography traditionally focused on fertility - the circumstances in which livebirths occur - with the aim of predicting population changes, in particular. Demographers also rapidly became interested in fecundity, developing concepts such as fecundability and definitive sterility. The measurement of fecundability is based on determination of the time to pregnancy (TTP), the basic tool of the epidemiologist. However, while demographers were developing methods for estimating the distribution of fecundability among couples based on TTP, epidemiologists turned to methods for analysing the role of diverse factors potentially influencing fecundity at the individual level.     

Two-stage functional mixed models for evaluating the effect of longitudinal covariate profiles on a scalar outcome

The Daily Hormone Study, a substudy of the Study of Women's Health Across the Nation (SWAN) consisting of more than 600 pre- and perimenopausal women, includes a scalar measure of total hip bone mineral density (BMD) together with repeated measures of creatinine-adjusted follicle stimulating hormone (FSH) assayed from daily urine samples collected over one menstrual cycle. It is of scientific interest to investigate the effect of the FSH time profile during a menstrual cycle on total hip BMD, adjusting for age and body mass index. The statistical analysis is challenged by several features of the data: (1) the covariate FSH is measured longitudinally and its effect on the scalar outcome BMD may be complex; (2) due to varying menstrual cycle lengths, subjects have unbalanced longitudinal measures of FSH; and (3) the longitudinal measures of FSH are subject to considerable among- and within-subject variations and measurement errors. We propose a measurement error partial functional linear model, where repeated measures of FSH are modeled using a functional mixed effects model and the effect of the FSH time profile on BMD is modeled using a partial functional linear model by treating the unobserved true subject-specific FSH time profile as a functional covariate. We develop a two-stage nonparametric regression calibration method using period smoothing splines. Using the connection between smoothing splines and mixed models, we show that a key feature of our approach is that estimation at both stages can be conveniently cast into a unified mixed model framework. A simple testing procedure for constant functional covariate effect is also proposed. The proposed methods are evaluated using simulation studies and applied to the SWAN data.     

Modeling human fertility in the presence of measurement error

The probability of conception in a given menstrual cycle is closely related to the timing of intercourse relative to ovulation. Although commonly used markers of time of ovulation are known to be error prone, most fertility models assume the day of ovulation is measured without error. We develop a mixture model that allows the day to be misspecified. We assume that the measurement errors are i.i.d. across menstrual cycles. Heterogeneity among couples in the per cycle likelihood of conception is accounted for using a beta mixture model. Bayesian estimation is straightforward using Markov chain Monte Carlo techniques. The methods are applied to a prospective study of couples at risk of pregnancy. In the absence of validation data or multiple independent markers of ovulation, the identifiability of the measurement error distribution depends on the assumed model. Thus, the results of studies relating the timing of intercourse to the probability of conception should be interpreted cautiously.     

Expression of prostasin serine protease and protease nexin-1 (PN-1) in rhesus monkey ovary during menstrual cycle and early pregnancy.

Serine proteases and their cognate serpin-class inhibitors are involved in the controlled proteolytic events during follicular development, ovulation, formation, and maintenance of the corpus luteum (CL). In this study, we investigated the expression patterns of prostasin serine protease and protease nexin-1 (PN-1), a serine protease inhibitor also called serpin-E2, in rhesus monkey ovaries during the menstrual cycle and early pregnancy, by using in situ hybridization and immunohistochemistry. Expression of prostasin was localized in oocyte, granulosa cells, and/or theca cells of early antral follicles and antral follicles, with high levels observed in preovulatory follicles. Prostasin was also localized at high levels of abundance in the CL during the menstrual cycle and early pregnancy. During the menstrual cycle, PN-1 was coordinately localized with prostasin in oocytes, granulosa cells, and theca cells of antral follicles and preovulatory follicles and in the CL. In addition, the PN-1 expression level in macaque CL during early pregnancy increased as pregnancy proceeded. We propose that prostasin may be involved in follicular development, ovulation, and CL formation, whereas PN-1 may be present to regulate the proteolysis in these processes.     

One-carbon metabolism during the menstrual cycle and pregnancy

Many enzymes in one-carbon metabolism (OCM) are up- or down-regulated by the sex hormones which vary diurnally and throughout the menstrual cycle. During pregnancy, estradiol and progesterone levels increase tremendously to modulate physiological changes in the reproductive system. In this work, we extend and improve an existing mathematical model of hepatic OCM to understand the dynamic metabolic changes that happen during the menstrual cycle and pregnancy due to estradiol variation. In particular, we add the polyamine drain on S-adenosyl methionine and the direct effects of estradiol on the enzymes cystathionine β-synthase (CBS), thymidylate synthase (TS), and dihydrofolate reductase (DHFR). We show that the homocysteine concentration varies inversely with estradiol concentration, discuss the fluctuations in 14 other one-carbon metabolites and velocities throughout the menstrual cycle, and draw comparisons with the literature. We then use the model to study the effects of vitamin B₁₂, vitamin B₆, and folate deficiencies and explain why homocysteine is not a good biomarker for vitamin deficiencies. Additionally, we compute homocysteine throughout pregnancy, and compare the results with experimental data. Our mathematical model explains how numerous homeostatic mechanisms in OCM function and provides new insights into how homocysteine and its deleterious effects are influenced by estradiol. The mathematical model can be used by others for further in silico experiments on changes in one-carbon metabolism during the menstrual cycle and pregnancy.     

Maternal Serum Meteorin Levels and the Risk of Preeclampsia

Background

Meteorin (METRN) is a recently described neutrophic factor with angiogenic properties. This is a nested case-control study in a longitudinal cohort study that describes the serum profile of METRN during different periods of gestation in healthy and preeclamptic pregnant women. Moreover, we explore the possible application of METRN as a biomarker.

Methods and Findings

Serum METRN was measured by ELISA in a longitudinal prospective cohort study in 37 healthy pregnant women, 16 mild preeclamptic women, and 20 healthy non-pregnant women during the menstrual cycle with the aim of assessing serum METRN levels and its correlations with other metabolic parameters. Immunostaining for METRN protein was performed in placenta. A multivariate logistic regression model was proposed and a classifier model was formulated for predicting preeclampsia in early and middle pregnancy. The performance in classification was evaluated using measures such as sensitivity, specificity, and the receiver operating characteristic (ROC) curve. In healthy pregnant women, serum METRN levels were significantly elevated in early pregnancy compared to middle and late pregnancy. METRN levels are significantly lower only in early pregnancy in preeclamptic women when compared to healthy pregnant women. Decision trees that did not include METRN levels in the first trimester had a reduced sensitivity of 56% in the detection of preeclamptic women, compared to a sensitivity of 69% when METRN was included.

Conclusions

The joint measurements of circulating METRN levels in the first trimester and systolic blood pressure and weight in the second trimester significantly increase the probabilities of predicting preeclampsia.     

Serum Phthalate Levels and Time to Pregnancy in Couples from Greenland,Poland and Ukraine

Phthalates are ubiquitous industrial chemicals that have been associated with altered reproductive function in rodents. Several human studies have reported an inverse association between male testosterone and phthalate levels. Our aim was to investigate time to pregnancy (TTP) according to serum levels of diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) metabolites in both partners. In 2002-2004 we enrolled 938 pregnant women and 401 male spouses from Greenland, Poland and Ukraine. Six oxidized metabolites of DEHP and DiNP were summarized for each of the two parent compounds to provide proxies of the internal exposure. We used Cox discrete-time models to estimate fecundability ratios (FR) and 95% confidence intervals (95% CIs) for men and women according to their proxy-DEHP or -DiNP serum levels adjusted for a fixed set of covariates.The FR was slightly elevated among women with high levels of DEHP (FR=1.14, 95% CI 1.00;1.30) suggesting a shorter TTP in these women. The FR was unrelated to DiNP in women, whereas the results for men were inconsistent pointing in opposite directions. First-time pregnant women from Greenland with high serum DiNP levels had a longer TTP. This study spanning large contrast in environmental exposure does not indicate adverse effects of phthalates on couple fecundity. The shorter TTP in women with high levels of DEHP metabolites is unexplained and needs further investigation.     

Modelling multiple ovulation,fertilization, and embryo loss in human fertility studies

Models of human fertility that incorporate information on timing of intercourse have assumed that a single ovum is released each menstrual cycle. These models are misspecified if two or more viable ova are sometimes released in a single cycle, which is known to occur in dizygotic twin pregnancies. In this paper, we propose a model for multiple ovulation in humans. We assume that the unobservable number of viable ova in each cycle follows a multinomial distribution. Successful fertilization of each ovum depends on the ability of the cycle to support a pregnancy and on the aggregate of a set of unobservable Bernoulli trials representing the fertilizing effects of intercourse on various days. Our model accommodates general covariate effects, allows for heterogeneity among couples, and accounts for a sterile subpopulation of couples. Information on early detection of pregnancy can be incorporated to estimate the probability of embryo loss. We outline a Markov chain Monte Carlo algorithm for estimation of the posterior distributions of the parameters. The methods are applied to data from a North Carolina pregnancy study, and applications to studies of assisted reproduction are described.     

Endometrial function in vervet monkeys (Cercopithecus aethiops): morphology,beta3 integrin and insulin-like growth factor binding protein-1 expression during the menstrual cycle and pregnancy in the normal and disrupted endometrium

The expression of endometrial beta3 integrin and insulin-like growth factor binding protein-1 (IGFBP-1) was studied in cycling and pregnant vervet monkeys. There were clear changes of beta3 integrin expression during the menstrual cycle, with the strongest immunostaining observed on day 26. Moderate to strong expression was observed during pregnancy. The expression of IGFBP-1 during the menstrual cycle was weak but upregulated during pregnancy with moderate to strong staining. The administration of a single dose of onapristone at 10 mg/kg on days 17, 21 and 22 of the menstrual cycle, followed by a biopsy on days 22, 22 and 26, respectively, and during pregnancy (34-44 days menstrual age) 24 h before the biopsy, disrupted and desynchronized the endometrium. However, no effect on beta3 integrin expression could be observed and staining reflected the untreated patterns. The same applied to IGFBP-1 except that during pregnancy the expression of this protein was reduced or abolished. The results suggest that beta3 integrin is associated with endometrial receptivity in vervet monkeys and that IGFBP-1 plays an important role during pregnancy in this species. The administration of onapristone appeared to only influence IGFBP-1 expression. To our knowledge, this is the first time that these endometrial proteins have been investigated in vervet monkeys. This study should therefore contribute to improving our understanding of the reproductive function of this species.     

Are stacked species distribution models accurate at predicting multiple levels of diversity along a rainfall gradient?

We use observed patterns of species richness and composition of ant communities along a 1000 mm rainfall gradient in northern Australian savanna to assess the accuracy of species richness and turnover predictions derived from stacked species distribution models (S‐SDMs) and constrained by macroecological models (MEMs). We systematically sampled ants at 15 sites at 50 km intervals along the rainfall gradient in 2012 and 2013. Using the observed data, we created MEMs of species richness, composition and turnover. We built distribution models for 135 of the observed species using data from museum collections and online databases. We compared two approaches of stacking SDMs and three modelling algorithms to identify the most accurate way of predicting richness and composition. We then applied the same beta diversity metrics to compare the observed versus predicted patterns. Stacked SDMs consistently over‐predicted local species richness, and there was a mismatch between the observed pattern of richness estimated from the MEM, and the pattern predicted by S‐SDMs. The most accurate richness and turnover predictions occurred when the stacked models were rank‐ordered by their habitat suitability and constrained by the observed MEM richness predictions. In contrast with species richness, the predictions obtained by the MEM of community similarity, composition and turnover matched those predicted by the S‐SDMs. S‐SDMs regulated by MEMs may therefore be a useful tool in predicting compositional patterns despite being unreliable estimators of species richness. Our results highlight that the choice of species distribution model, the stacking method used, and underlying macroecological patterns all influence the accuracy of community assembly predictions derived from S‐SDMS.     

Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome

A great number of case reports on concordant and discordant twins with oculo-auriculo-vertebral spectrum (OAVS) suggest that there might be an association between reproductive abnormalities, twinning and OAVS. The etiology of OAVS is unknown, but may involve epigenetic dysregulation of the oocyte or early embryo. We collected data on fertility and pregnancy outcome of 72 parents of patients with sporadic OAVS. We also evaluated prospective follow-up data on 3.372 fetuses and children conceived by intracytoplasmatic sperm injection (ICSI). Parental age, duration of menstrual cycle and the incidence of spontaneous abortion was not different when compared to the German population. However, there is an excess of parents who have used assisted reproductive techniques (ART; retrospective P = 0.038, prospective P = 0.023) and an excess of twins among naturally conceived patients with OAVS (P = 0.0025). An excess of ART conceptions and monozygotic twinning in OAVS is compatible with the concept of overripeness ovopathy as proposed by Jongbloet (Maandschr Kindergeneeskd 36:352–367, 1968).     

The role of temperature and other factors in predicting the pattern of bovine Ostertagia spp. Infective larvae on pasture

A prediction model based on predicting the development time of the egg to the infective stage of the parasite O. ostertagi using temperature is described for bovine ostertagiasis. Two isolates of Ostertagia spp., having different capacities for infectivity and fecundity are considered. Predictions based on the capacities of each of the two isolates are compared with that observed in an animal management system studied in 1979. Infectivity and fecundity are shown to markedly influence the predicted patterns of pasture contamination.     

Temperament and ovarian reproductive hormones in women: evidence from a study during the entire menstrual cycle

Personality and temperament were hypothesized to function as important factors affecting life history strategies. Recent research has demonstrated the association between temperamental traits and reproduction in humans, however, the underlying mechanisms are still poorly understood. This study presents evidence for an association between temperamental traits and woman's fecundity, as indicated by levels of ovarian steroid hormones during the menstrual cycle. On a large sample of urban, reproductive age women (n = 108) we demonstrated that activity, endurance and emotional reactivity are associated with levels of estrogen and with a pattern of change of progesterone levels. Women high in activity, high in endurance and low in emotional reactivity had up to twice as high estradiol levels and more favorable progesterone profiles as women low in activity, low in endurance and high in emotional reactivity. The temperamental traits we measured highly overlap with extraversion, neuroticism and negative emotionality that were reported to correlate with reproductive success. Our findings thus suggest a possible explanation for these relationships, linking personality and women's reproductive success through a hormonal pathway.     

Global climate cycles and cyclones: consequences for rainfall patterns and lemur reproduction in southeastern Madagascar

Most studies that examine the influence of climatic change on flora and fauna have focused on northern latitudes; however, there is increasing recognition that tropical regions are also being affected. Despite this, regions such as Madagascar, which are rich in endemic biodiversity but may have low adaptive capacity to climatic change, are poorly represented in studies examining the effects of climate variability on biota. We investigated how El Niño Southern Oscillations (ENSO) influence precipitation patterns in the rainforest region of southeastern Madagascar (1962–2006) and then constructed models to assess the potential contribution of climatic variables on the reproductive parameters of the Milne Edward's sifaka, a threatened lemur species (Propithecus edwardsi), over a 20‐year period. The Southern Oscillation Index of sea surface temperature (SST) anomalies in the tropical Pacific was associated with precipitation patterns including wetter wet seasons during warmer phases and drier dry seasons following cooler phases. The best‐supported models of lemur fecundity (female offspring per female that survive to 1 year of age per year) included cyclone presence during gestation and ENSO phase before conception and during the first 6 months of life. Models also suggested that heavy rains during gestation may limit birth rates and that prolonged drought during female lactation may limit first year offspring survival; although these variables were given little importance for predicting overall fecundity relative to ENSO phases and cyclone presence. Our results linking lemur reproduction with climatic variability suggest that climatic changes may be an additional threat to Madagascar's unique and already endangered flora and fauna. The association between precipitation in southeastern Madagascar and SST anomalies in the tropical Pacific suggests that dynamics of wildlife populations even in tropical areas such as Madagascar can be affected by global climate cycles making them potentially vulnerable to global climate change.     

Characterization of periostin expression in human endometrium and endometriotic lesions

Objective(s): To investigate the expression of periostin in the eutopic and ectopic endometrium of women diagnosed as endometriosis and evaluate the role of periostin in the pathogenesis of endometriosis. Study design: In this study, the expression of periostin was evaluated in the endometrial specimens from 35 women diagnosed as endometriosis and from 30 healthy women. To assess the presence and localization of periostin throughout the menstrual cycle in both eutopic and ectopic endometrium of women with endometriosis, microscopic evaluation was conducted. It was also subsequently compared with normal endometrium. Results: In the eutopic and ectopic endometrium of women with endometriosis, immunoreactivities of periostin increased compared with those of normal endometrium. We also observed a cyclic variation in the eutopic stromal periostin immunoreactivity throughout their menstrual cycle because higher H score values were observed in the proliferative phase than those in the secretory phase. Conclusion(s): These findings indicated that periostin may be involved in the pathophysiology of endometriosis.     

Cues to sex- and stress-hormones in the human male face: functions of glucocorticoids in the immunocompetence handicap hypothesis

The stress-linked version of the immunocompetence handicap hypothesis has been proposed to account for inconsistencies in relationships between testosterone and immune response. The model has received some support from studies demonstrating roles of stress hormones in relationships between testosterone, immune function and secondary sexual ornamentation. Such work, however, has relied on artificial elevation of testosterone so may not reflect relationships in natural populations. We created human male facial stimuli on the basis of naturally co-occurring levels of salivary testosterone and the stress hormone cortisol. In Study 1 we tested female preferences for male faces with cues to combinations of the hormones across the menstrual cycle, and in Study 2 we tested perceptions of health and dominance in a novel set of facial stimuli. Females preferred cues to low cortisol, a preference that was strongest during the fertile phase of the menstrual cycle. The effects of cortisol on attractiveness and perceived health and dominance were contingent upon level of testosterone: the effects of the stress hormone were reduced when testosterone was high. We propose explanations for our results, including low cortisol as a cue to a heritable component of health, attractiveness as a predictor of low social-evaluative threat (and, therefore, low baseline cortisol) and testosterone as a proxy of male ability to cope efficiently with stressors.     

Secretory proteins and growth factors of the baboon (Papio anubis) uterus: potential roles in pregnancy.

The primate endometrium undergoes distinct morphological changes during the menstrual cycle. These alterations are regulated by the steroid hormones, estrogen and progesterone. Several lines of evidence suggest that some of these hormonally induced changes may be modulated by growth factors. Our studies have focused on characterizing the secretory activity of the uterine endometrium associated with these hormonally regulated morphological changes during the menstrual cycle and pregnancy in the baboon. Additionally, we have also attempted to study the regulation of specific growth factors and their receptors. In this review we present evidence to indicate that growth factor receptors for insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF), and secretory proteins, insulin-like growth factor binding protein-1 (IGFBP-1) and retinol binding protein (RBP), which are present in the glandular epithelium during the menstrual cycle, undergo cell-specific changes in gene expression at the implantation site during pregnancy. We postulate that these alterations in growth factor receptor and secretory protein expression are conceptus modulated and may play important regulatory roles during trophoblast invasion and decidualization.     

Sporadic sexual behavior and menstrual cycle length in women

In an initial study of 248 university students prospective double-blind monitoring of sexual behavior and menses onsets showed that sporadic (less than regular weekly) sexual activity was associated with aberrant menstrual cycle lengths. This study examines the sample of sporadically active women for behavioral correlates of aberrant cycle lengths. It is shown that women reporting a high frequency of sexual activity (though in a sporadic pattern) showed a higher incidence of aberrant cycle lengths than women reporting a low frequency of sporadic coitus. Stable ongoing sexual behavior patterns appear to associate with a different endocrine background than less stable, sporadic sexual patterns.     

Menstrual Cycle Phase Does Not Predict Political Conservatism

Recent authors have reported a relationship between women''s fertility status, as indexed by menstrual cycle phase, and conservatism in moral, social and political values. We conducted a survey to test for the existence of a relationship between menstrual cycle day and conservatism.2213 women reporting regular menstrual cycles provided data about their political views. Of these women, 2208 provided information about their cycle date, 1260 provided additional evidence of reliability in self-reported cycle date, and of these, 750 also indicated an absence of hormonal disruptors such as recent hormonal contraception use, breastfeeding or pregnancy. Cycle day was used to estimate day-specific fertility rate (probability of conception); political conservatism was measured via direct self-report and via responses to the "Moral Foundations” questionnaire. We also recorded relationship status, which has been reported to interact with menstrual cycle phase in determining political preferences.We found no evidence of a relationship between estimated cyclical fertility changes and conservatism, and no evidence of an interaction between relationship status and cyclical fertility in determining political attitudes. Our findings were robust to multiple inclusion/exclusion criteria and to different methods of estimating fertility and measuring conservatism. In summary, the relationship between cycle-linked reproductive parameters and conservatism may be weaker or less reliable than previously thought.