Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study
Mikolajczyk, R. T., Stanford, J. B., & Ecochard, R. (2008). Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study. Reproductive biology and endocrinology : RB&E, 6(1), 61. https://doi.org/10.1186/1477-7827-6-61
Mikolajczyk RT, Stanford JB, Ecochard R. Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study. Reprod Biol Endocrinol. 2008;6(1):61. doi:10.1186/1477-7827-6-61
Mikolajczyk, R. T., et al. "Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study." Reproductive biology and endocrinology : RB&E, vol. 6, no. 1, 2008, pp. 61.
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Follicle size varies by cycle in women with normal fertility
Researchers scanned the ovaries of 107 women with normal fertility at eight European centers. Follicles grew at about the same speed across these women. Follicle size before ovulation changed from one cycle to the next in the same women. About 4 out of 10 cycles had a follicle under 19 mm the day before ovulation.
Key Findings
The analysis used 533 ultrasound measurements from 282 cycles in 107 women with normal fertility, recruited at 8 centers in 4 European countries.
Analysis showed no evidence for a center effect on growth rate or maximum follicular diameter. Growth rate was homogeneous across women and across cycles.
Maximum follicular diameter varied significantly between cycles, with no indication of differences between women. The mean was 20.48 mm, with a standard deviation of 3.98.
About 40% of cycles showed a follicle under 19 mm on the day before ovulation, in the observed data.
Cycle length showed no correlation with follicle size before ovulation in this sample (Spearman's rho = 0.02, p-value = 0.7).
Interpretation
The study is a secondary analysis of a prospective cohort, so it maps patterns and cannot show what causes them. The women had normal fertility, were experienced with natural family planning methods, and lived in Europe. The authors say including women who have trouble getting pregnant may have produced differences between women. Most scans came one to two days before ovulation, and many cycles had only one or two measurements, which may have hidden differences in growth rate. The authors state it is unclear whether a small follicle matters for women with no known fertility problems.
RRM Context
The authors note that ultrasound checks for couples who have trouble getting pregnant often rest on a single cycle. Their results suggest one cycle could give a misleading picture of follicle growth. Follicle size at ovulation varied within each woman, so a single scan describes only that cycle. Restorative reproductive medicine reads findings across several cycles of charting.
Our editorial summary of this paper, not the article's abstract.
Abstract
Background
To assess the amount of variability in ovarian follicular growth rate and maximum follicular diameter related to different centers, women and cycles of the same women in a multicenter observational study of follicular growth.
Methods
Secondary analysis of a prospective cohort study from eight centers in Europe. There were 533 ultrasound examinations in 282 cycles of 107 women with normal fertility. A random effects model with center, woman and cycle as hierarchical units of variation was used to analyze mean follicular diameter on days preceding ovulation.
Results
Follicular growth did not differ by center. There was homogenous growth across women and cycles, and the maximum follicular diameter before ovulation varied substantially across cycles but not across women. Many (about 40%) women had small maximum follicular diameter on the day before ovulation (<19 mm). Pre-ovulatory cycle length was not related to maximum follicular diameter.
Conclusion
In normal fecundity, there is a substantial variation in maximum follicular diameter from cycle to cycle based on variation in the duration of follicular development, but the variation could not be explained by different characteristics of different women. Explanation of variation in follicular growth has to be found on the cycle level.
Minjeur M et al., 2026·Journal of Restorative Reproductive Medicine·Free to read
Infertility is a clinical condition that is recognized by the symptom of an inability to conceive through sexual intercourse or to sustain a pregnancy, with that symptom indicating underlying male and/or female pathology.
This definition of infertility was developed through a structured, consensus-informed process involving broad stakeholder engagement. Initially, multiple definitions currently used by various medical professional organizations were reviewed, and a definition document was drafted and submitted to the Board of Directors of the International Institute for Restorative Reproductive Medicine (IIRRM). All IIRRM members were invited to provide feedback on the draft. Approximately 2,500 individuals and 44 organizations from 92 countries were then invited to review the proposed document, representing clinical, scientific, patient, policy, and advocacy perspectives. Submitted comments were reviewed thematically, with suggested revisions evaluated for clarity, clinical relevance, inclusiveness, and consistency with contemporary restorative reproductive medicine. Following this review, 3 substantive changes, 18 minor changes, and 15 citation corrections were incorporated into the final draft which resulted in a revised definition intended to better reflect the medical, social, and practical realities of modern infertility evaluation and care. Final approval by the IIRRM Board of Directors was unanimous.
Bouchard TP et al., 2026·Reproductive biomedicine online·Free to read
Does formation of the corpus luteum help to identify the day of ovulation on ultrasound when follicular collapse is missed, and how reliable are sonographers versus a review panel in identifying the day of ovulation on ultrasound? Sonographers in a clinic in Canada performed serial endovaginal ultrasound scans (six to eight per cycle) to identify the day of ovulation in regularly cycling women (n = 40) who were followed for one to five cycles (n = 85). The day of ovulation was identified by: (i) identification of the dominant follicle; (ii) disappearance of the dominant follicle; and (iii) identification and dating of the corpus luteum. The main outcome measures were inter-rater reliability between two sonographers, and Bland-Altman agreement between the supervising sonographer and a panel that reviewed each scan to identify the day of ovulation. Of the 85 menstrual cycles reviewed, two cycles did not have sufficient data to date ovulation, one cycle showed an incidental dermoid cyst, and 11 cycles showed anovulatory patterns. This left a total of 71 cycles (84%) for which intra-rater reliability between two sonographers for identifying the day of ovulation was high (intraclass correlation coefficient = 0.99, P < 0.0001), and Bland-Altman agreement showed no significant difference in the estimated day of ovulation between the supervising sonographer and the panel (t = -0.28, P = 0.78). Corpus luteum criteria were necessary to help identify the day of ovulation in 14 of 71 cycles (20%). The estimated day of ovulation can be determined reliably on ultrasound by trained sonographers using collapse of the dominant follicle and formation of the corpus luteum based on six to eight scans per cycle.
Kahn LG et al., 2026·JAMA Network Open·Free full text on PubMed Central
Increasing numbers of children are conceived using infertility treatment; concerns remain about potential effects on child neurodevelopment. To evaluate whether infertility treatment is associated with child neurodevelopment and whether such an association may be attributable to underlying subfecundity. DESIGN, SETTING, This cohort study was conducted among mother-child dyads in the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) Cohort, with infants conceived between 1998 and 2022. Associations of subfecundity and infertility treatment with neurodevelopmental outcomes were assessed among children ages 2 to 10 years. Data were analyzed from May 14, 2025, to March 31, 2026. Subfecundity was defined as prior consultation for, treatment of, or diagnosis of infertility for either partner; at least 2 prior miscarriages; or ever having had unprotected heterosexual intercourse for 12 months without conceiving. Infertility treatment was categorized as in vitro fertilization (IVF) or non-IVF treatment. Harmonized caregiver responses to the Strengths and Difficulties Questionnaire and the Child Behavior Checklist yielded continuous raw scores for externalizing and internalizing problems. The total raw Social Responsiveness Scale (SRS) score quantified autism-like symptoms. Caregivers reported physician diagnosis of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Among 15 382 mother-infant dyads, there were 14 191 unique maternal participants (mean [SD] age at delivery, 30.9 [5.33] years; 8780 parous participants [57.1%]). ASD and ADHD were diagnosed in 876 offspring (7.6%) and 819 offspring (7.1%), respectively. In generalized linear models, subfecundity was associated with higher externalizing problem and SRS scores among all pregnancies (externalizing problems: b = 0.47 [95% CI, 0.14-0.81]; SRS score: b = 1.08 [95% CI, 0.01-2.14]) and when restricted to natural conceptions (externalizing problems: b = 0.45 [95% CI, 0.07-0.83]; SRS score: b = 1.12 [95% CI, -0.09 to 2.34]). Offspring of parents with subfecundity had higher odds of ASD (overall: odds ratio [OR], 1.27 [95% CI, 1.03-1.57]; natural conceptions: OR, 1.31 [95% CI, 1.04-1.64]). Children conceived via non-IVF treatment had higher odds of ADHD compared with those conceived via natural conception with subfecundity (OR, 1.77 [95% CI, 1.16-2.68]) or without subfecundity (OR, 1.54 [95% CI, 1.05-2.25]). There were no significant associations for IVF treatment. In this large US cohort study, subfecundity was associated with elevated scores for caregiver-reported symptoms of behavioral problems and higher odds of ASD diagnosis, independent of infertility treatment. Non-IVF treatment was associated with ADHD, warranting further research into specific indications for treatment that may increase risk of offspring neurodevelopmental problems.
Stanford JB et al., 2026·Frontiers in Reproductive Health·Free full text on PubMed Central
Background The total fertility rate (TFR) in most developed countries has been declining for decades. In the United States (U.S.), the total fertility rate has remained below replacement level since 2007. Subfertility affects at least 15% of women or couples over their reproductive lifespan and contributes to reduced TFR. Restorative reproductive medicine (RRM) is a medically based approach to subfertility care that can be delivered in primary care settings to increase live birth rates. Objective To estimate the theoretical impact of use of RRM among subfertile couples in the United States. Methods We conducted a simulation study. Model inputs included the number of women of reproductive age in the United States by 5-year age groups; current age-specific and total fertility rates; the proportion of women in each age group with subfertility; estimated spontaneous live birth rates among women with subfertility; and age-specific crude live birth rates with RRM treatment. We evaluated fifteen scenarios including sensitivity analyses: two different varying assumptions for spontaneous conception (25% vs. 50%), two levels of RRM utilization among subfertile women (20% vs. 50%), three different estimates of the number of subfertile women who would be potentially eligible for RRM treatment, and 4 different levels of effectiveness (live birth) from RRM treatment. Results The baseline TFR in the United States was 1.77 during 2015-2019, and 13.5% of women ages 20-44 were estimated to have subfertility. In a conservative scenario (50% spontaneous births; 20% RRM utilization; married women trying to conceive for at least 12 months, 20.7% RRM live births), the TFR increased to 1.79, representing a 1.0% relative increase (absolute +0.02). In an optimistic scenario (25% spontaneous births; 50% RRM utilization; all subfertile women), the TFR increased to 2.02, a 14.5% relative increase (absolute +0.26), approaching replacement-level fertility. Conclusion Simulation results suggest that expanding access to RRM within primary care settings could meaningfully increase the U.S. TFR, by reducing unresolved subfertility. Realizing this potential would require policy and health system changes to address workforce capacity, insurance coverage, and equitable access. These findings underscore the potential contribution of non-IVF fertility care pathways in addressing population-level fertility decline.
Fehring RJ et al., 2006·J Obstet Gynecol Neonatal Nurs·Free to read
To determine variability in the phases of the menstrual cycle among healthy, regularly cycling women.
A prospective descriptive study of a new data set with biological markers to estimate parameters of the menstrual cycles. One hundred forty one healthy women (mean age 29 years) who monitored 3 to 13 menstrual cycles with an electronic fertility monitor and produced 1,060 usable cycles of data. Outcomes: Variability in the length of the menstrual cycle and of the follicular, fertile, and luteal phases, and menses. The estimated day of ovulation and end of the fertile phase was the peak fertility reading on the monitor (i.e., the urinary luteinizing hormone surge). Mean total length was 28.9 days (SD = 3.4) with 95% of the cycles between 22 and 36 days. Intracycle variability of greater than 7 days was observed in 42.5% of the women. Ninety-five percent of the cycles had all 6 days of fertile phase between days 4 and 23, but only 25% of participants had all days of the fertile phase between days 10 and 17. Among regularly cycling women, there is considerable normal variability in the phases of the menstrual cycle. The follicular phase contributes most to this variability.
Malliou-Becher MN et al., 2026·Human reproduction (Oxford, England)
What are the variations in ovulation time and menstrual cycle characteristics among and within various individuals over the course of 12 menstrual cycles? There are considerable variations in both cycle length and ovulation time, with pronounced intra-individual variability over a 12-cycle observation period. Although it is commonly believed that healthy women have regular cycles with a predictable mid-cycle ovulation, more recent research shows a significant variation in cycle length and ovulation time. Previous studies have focused only on cycle length, often excluding cycles outside the 25-35-day range, thus limiting the understanding of natural variation; they have also lacked precise ovulation diagnostics or included small sample sizes, making it difficult to capture the full scope of cycle and ovulation variability. Similarly, a recent big data study, while valuable, was limited by a self-selected group and the absence of accurate ovulation diagnostics, reducing its generalizability. STUDY DESIGN, SIZE, This study was designed as a prospective long-term observational study, which involved collecting data from 1923 women with a total of 43 999 menstrual cycles from January 1985 to July 2019. After fulfilling the inclusion criteria, the main group consisted of 1051 women, all of whom contributed data for 12 cycles (12 612 cycles), including 420 conception cycles. PARTICIPANTS/MATERIALS, SETTING, Participants in the study were between 18 and 44 years of age at study entry and did not take any reproductive hormones. Women who were postpartum, breastfeeding, amenorrheic, or within a 3-month period after stopping hormonal contraception were excluded. Participants agreed to keep cycle records according to the symptothermal method, 'Sensiplan'. Ovulation time was determined using an evidence-based algorithm based on evaluating cervical mucus patterns and basal body temperature shifts, with ovulation time defined as the day before the temperature rise. Data analysis was descriptive, using absolute and relative frequencies, standard deviation, percentiles, and ranges. Age dependency was assessed using unpaired sample t-tests and one-way ANOVA. Linear regression was used to assess long-term trends. MAIN In 62.4% of women, cycle lengths varied by 1 week or more within 12 cycles. Accordingly, the time of ovulation varied by 1 week or more within 12 cycles in 54.8% of women, with 96.5% experiencing fluctuations of 4 days or more over the 12 months. The median spontaneous cycle length was 28 days, with a mean of 29.66 days (SD = 7.55). Only 52.7% of women consistently had cycle lengths between 23 and 35 days across all 12 cycles. Ovulation occurred most frequently between Days 12 and 16, with almost half of conceptions (45.7%) occurring after Day 16. A one-way analysis of variance revealed a significant reduction in mean cycle length with increasing age (P < 0.001), showing the shortest median cycle length of 27 days being in women aged 40-44 years. Age also impacted ovulation time, with women aged 35-39 years showing more stable ovulation patterns compared to younger women. Over the 34-year study period, average cycle length increased slightly but significantly (β = 0.0161, P = 0.0306), corresponding to approximately half a day. Intra-individual variability also showed a slight, but non-significant, upward trend (β = 0.0262, P = 0.2173). LIMITATIONS, Comorbidities such as hyperprolactinemia, obesity, and PCOS were not systematically excluded. However, by including only women with at least 12 cycles, the study largely avoided severe hormonal disorders. This study highlights the considerable individual variation of ovulation time and cycle length over 12 menstrual cycles. These findings contribute to a better understanding of fertility awareness, and highlight the implications for family planning and reproductive health management. STUDY FUNDING/COMPETING INTEREST(S): The authors declare no conflicts of interest. No funding was provided. N/A.
Henry S et al., 2024·Hum Reprod·Free full text on PubMed Central
What is the relative length variance of the luteal phase compared to the follicular phase within healthy, non-smoking, normal-weight, proven normally ovulatory, premenopausal women with normal-length menstrual cycles? Prospective 1-year data from 53 premenopausal women with two proven normal-length (21-36 days) and normally ovulatory (≥10 days luteal) menstrual cycles upon enrollment showed that, despite 29% of all cycles having incident ovulatory disturbances, within-woman follicular phase length variances were significantly greater than luteal phase length variances. Many studies report menstrual cycle variability, yet few describe variability in follicular and luteal phase lengths. Luteal lengths are assumed 'fixed' at 13-14 days. Most studies have described follicular and luteal phase variability between-women. STUDY DESIGN, SIZE, Duration: This study was a prospective, 1-year, observational cohort study of relative follicular and luteal phase variability both between and within community-dwelling women with two documented normal-length (21-36 days) and normally ovulatory (≥10 days luteal phase) menstrual cycles prior to enrollment. Eighty-one women enrolled in the study and 66 women completed the 1-year study. This study analyzed data from 53 women with complete data for ≥8 cycles (mean 13). PARTICIPANTS/MATERIALS, SETTING, Participants were healthy, non-smoking, of normal BMI, ages 21-41 with two documented normal-length (21-36 days) and normally ovulatory (≥10 days luteal phase) menstrual cycles prior to enrollment. Participants recorded first morning temperature, exercise durations, and menstrual cycle/life experiences daily in the Menstrual Cycle Diary. We analyzed 694 cycles utilizing a twice-validated least-squares Quantitative Basal Temperature method to determine follicular and luteal phase lengths. Statistical analysis compared relative follicular and luteal phase variance in ovulatory cycles both between-women and within-woman. Normal-length cycles with short luteal phases or anovulation were considered to have subclinical ovulatory disturbances (SOD). Main The 1-year overall 53-woman, 676 ovulatory cycle variances for menstrual cycle, follicular, and luteal phase lengths were 10.3, 11.2, and 4.3 days, respectively. Median variances within-woman for cycle, follicular, and luteal lengths were 3.1, 5.2, and 3.0 days, respectively. Menstrual cycles were largely of normal lengths (98%) with an important prevalence of Sod: 55% of women experienced >1 short luteal phase (<10 days) and 17% experienced at least one anovulatory cycle. Within-woman follicular phase length variances were greater than luteal phase length variances (P < 0.001). However, follicular (P = 0.008) and luteal phase length (P = 0.001) variances, without differences in cycle lengths, were greater in women experiencing any anovulatory cycles (n = 8) than in women with entirely normally ovulatory cycles (n = 6). LIMITATIONS, Limitations of this study include the relatively small cohort, that most women were White, initially had a normal BMI, and the original cohort required two normal-length and normally ovulatory menstrual cycles before enrollment. Thus, this cohort's data underestimated population menstrual cycle phase variances and the prevalence of SOD. Our results reinforce previous findings that the follicular phase is more variable than the luteal phase in premenopausal women with normal-length and ovulatory menstrual cycles. However, our study adds to the growing body of evidence that the luteal phase is not predictably 13-14 days long. STUDY FUNDING/COMPETING INTEREST(S): This medical education project of the University of British Columbia was funded by donations to the Centre for Menstrual Cycle and Ovulation Research. The authors do not have any conflicts of interest to disclose. N/A.
Ecochard R et al., 2000·Human reproduction (Oxford, England)
This study was undertaken to establish whether ovulation in humans alternates consistently from right to left ovary in successive cycles and whether the site of ovulation affects the next cycle length or the hormonal profiles. A total of 199 cycles in 80 normally fertile women were studied. The volunteers were monitored with ultrasonography to determine the day and side of ovulation and to calculate follicular and luteal phase lengths. Urinary hormone concentrations were also assayed. Right-sided ovulations occurred in 104 of the 199 cycles (52.3%; not significantly different from 50%). Alternate ovulations occurred in 61 of the 119 pairs of succeeding cycles (51.3%, not significant). The follicular phase length in contralateral ovulation (14.59 +/- 0.33 days; mean +/- SEM) did not differ significantly from that of ipsilateral ovulation (14.59 +/- 0. 37 days). There were also no significant differences in urinary concentrations of oestrone-3-glucuronide, pregnanediol-3alpha glucuronide, follicle stimulating hormone, and luteinizing hormone between ipsilateral and contralateral ovulation in either early follicular, peri-ovulatory or luteal phase of the cycle. It is concluded that in normally fertile women, the cycle length and the hormonal profile are independent of the, most probably random, site of ovulation.
Joe Stanford, Joey Stanford, J Stanford, R Ecochard
PMID 19077200 19077200 DOI 10.1186/1477-7827-6-61 10.1186/1477-7827-6-61 Ecochard et al. 2008, Ecochard 2008
Cite this article
Mikolajczyk, R. T., Stanford, J. B., & Ecochard, R. (2008). Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study. Reproductive biology and endocrinology : RB&E, 6(1), 61. https://doi.org/10.1186/1477-7827-6-61
Mikolajczyk RT, Stanford JB, Ecochard R. Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study. Reprod Biol Endocrinol. 2008;6(1):61. doi:10.1186/1477-7827-6-61
Mikolajczyk, R. T., et al. "Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study." Reproductive biology and endocrinology : RB&E, vol. 6, no. 1, 2008, pp. 61.
