Modeling Fertile Window Differences Across the Reproductive Lifespan with Quantitative Urine Hormone Monitoring of the Menstrual Cycle

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Bouchard, Richard J. Fehring, Maria Meyers, Theresa Stujenske, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6669318/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Reproductive hormones of the fertile window are often referenced to women in regular cycles, but this may not be representative of the hormonal profiles of women in different circumstances like polycystic ovarian syndrome, the postpartum period, and the perimenopause transition. This observational cohort study sought to identify the variability in the hormones of the fertile window in various reproductive categories and to establish potential thresholds for each category based on hormone measurements with the Mira urinary hormone monitor. Results A total of 57 women (ages 22–51) in various circumstances (regular cycles, polycystic ovarian syndrome, postpartum and perimenopause) tracked Mira urine hormone measurements (estrone-3-glucuronide, luteinizing hormone, pregnanediol glucuronide), contributing 444 cycles of data. Using additive mixed models, hormone values were stratified by the four different reproductive categories. The perimenopause and polycystic ovararian syndrome groups demonstrated relative hypoestrogenic states, while the perimenopause group showed low luteal pregnanediol glucuronide and the polycystic ovarian syndrome group showed high luteal pregnanediol glucuronide. The perimenopause group had higher luteinizing hormone values throughout the whole cycle. Conclusion The fertile window hormone thresholds vary depending on a woman’s specific reproductive category. Women in different circumstances should not necessarily use the same hormonal thresholds for the fertile window and ovulation. A larger dataset with ultrasound correlation to ovulation is required to delineate the fertile window with more precision. Hormone differences across the menstrual cycle could be used for targeted treatments in polycystic ovarian syndrome and perimenopause women. Menstrual Cycle Ovulation Estrone-3-glucuronide (E13G) luteinizing hormone (LH) Pregnanediol glucuronide (PDG) Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background In a recent clinical opinion article [1], Cromack and Walter described the rapidly expanding Femtech industry with a focus on wearables and personal devices to identify the fertile window. Marketing and use of these devices for menstrual cycle monitoring is outpacing evidence-based validation studies [1]. Of historic interest, the same climate of change was present over three decades ago at a conference sponsored by the World Health Organization [2]. Multiple studies presented the use of at-home tests to track the fertile window [3–6], including a new urine fertility monitor to avoid pregnancy[7]. By that time, ultrasound studies had already been published outlining criteria for the detection of ovulation [8], and at this conference Flynn[9] described ovulation on ultrasound in breastfeeding women. The current study recapitulates this early work defining the fertile window and ovulation in various reproductive circumstances with an emphasis on the menstrual cycle as a vital sign for women’s health [10–12]. However, a vital sign requires having validation, for example, valid tools to track bleeding [13], ovulation [1], and confirmation of whether ovulation has occurred [14,15]. This vital sign needs to take into account variability in cycle length[16] and phases of the menstrual cycle in various reproductive circumstances, not just regularly cycling women [17,18]. Monitoring the menstrual cycle parameters in postpartum and perimenopause women as well as those with polycystic ovarian syndrome (PCOS) using the new Mira fertility monitor was the aim of the present study, to understand the variability in hormones across the continuum of the menstrual cycle [19]. The Mira monitor measures the urinary metabolites of follicle-stimulating hormone (FSH), of estradiol in the form of estrone-3-glucuronide (E 1 3G), of luteinizing hormone (LH), and of progesterone in the form of pregnanediol glucuronide (PDG) previously described in detail [20]. Urine hormone monitoring provides a non-invasive means of assessing underlying ovulatory function and menstrual cycle physiology[21] and Mira E 1 3G has been compared to serum estradiol in a recent study [22]. In the follicular phase of the menstrual cycle, rising levels of estrogen from the dominant follicle trigger a surge of luteinizing hormone from the anterior pituitary gland. This LH surge typically occurs 24–48 hours before ovulation, leading to the release of a mature egg [23]. Following ovulation, the luteinized follicle (corpus luteum) produces progesterone, which is essential for preparing the endometrium for potential implantation [24]. Urine and serum reproductive hormone measurements demonstrate strong agreement [25], but unlike serum testing, which provides a measure of reproductive hormone levels at a single time point, daily first morning urine hormone testing enables a real-time analysis of hormone levels across the entire menstrual cycle. This could refine our understanding of menstrual cycle parameters, including follicular and luteal phase length, the fertile window, and timing of ovulation [20,26–28]. The Mira monitor was chosen for the current study based on pilot data demonstrating good acceptability and ease of use by participants [20]. Tracking the fertile window is challenging in women with polycystic ovarian syndrome (PCOS). The diagnosis of PCOS is based on meeting two of the following three consensus-based Rotterdarm criteria [29]: irregular cycles, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound. With the cycle irregularities of PCOS, related to estradiol dysregulation [30] and abnormal gonadotropin LH secretion [31], the Mira monitor has the potential to provide clarity to women with PCOS regarding their hormone patterns by identifying whether an LH rise is appropriately followed by a progesterone rise suggesting corpus luteum formation. It may also provide a way to track pre- and post-treatment interventions for PCOS. Another challenging time to navigate the menstrual cycle is during postpartum amenorrhea and the first few transition cycles that are longer than usual [32]. The ClearBlue Fertility Monitor (CBFM) has been used in combination with the Marquette Method of family planning to track the return of fertility postpartum [33,34], but does not provide quantitative hormone data so may incorrectly identify the day of ovulation [35]. Using the Mira monitor to track E 1 3G, LH and PDG can help to identify which rises in E 1 3G and LH may potentially be ovulatory, with rising PDG to confirm the first ovulation postpartum. This would inform the postpartum return of fertility [36]. Finally, the perimenopause transition also presents difficulties related to irregular cycles, variable hormonal patterns and disturbing vasomotor symptoms due to these hormonal changes [37]. This transition has been categorized in detail based on the Stages of Reproductive Aging Workshop (STRAW) in 2012 [38]. Instead of using a woman’s age as a marker for infertility, this system takes into account cycle length variability to describe reproductive stage and fertility. However, rather than just identifying cycle length variability, the Mira monitor may help to better delineate the hormonal transition as proposed in a recent case series [39]. In the current study, quantitative urine hormones (E 1 3G, LH and PDG; due to insufficient FSH data, FSH was not included), referenced to the LH surge day (the estimated day of ovulation) and confirmed by a rise in PDG, were compared between four reproductive categories to outline group differences in hormones during the fertile window and phases of the menstrual cycle. Methods Aim, Design and Setting This was an observational cohort study with prospective data collection using the Mira Monitor in various circumstances, with ethical approval by the Marquette University research ethics board (HR 4276, April 4, 2023) in accordance with the Declaration of Helsinki. Inclusion criteria were: (1) English-speaking women between the ages of 18 and 52, (2) using their own Mira monitor and test wands, in (3) the four reproductive categories (regular cycles, PCOS, postpartum and perimenopause). Women were excluded if they: (1) were on hormonal medications that would impact ovulation, (2) had a previous hysterectomy or oophorectomy. All participants provided informed consent to participate. Recruitment was initiated via email to Marquette Method health care providers who teach women how to monitor their menstrual cycles. Eligible participants were asked to email the principal investigator (MS), who sent them a description of the study and links to complete: a consent form, a demographics form, and a chart data form. Participants consented to share their hormone data from an online Mira portal for health care providers. Forms and chart data were uploaded to a secure, private Marquette University OneDrive folder. Data was collected over 1 year, after which access to the portal was discontinued. Definitions of reproductive categories The definition of regular cycles was based on previously established criteria,[40] with consistent cycles (≤ 7 days variation between cycles) that were 24–38 days in length. Postpartum women were defined as being within delivery of a child in the last year and within the first 6 transition cycles postpartum after the initial postpartum amenorrhea, they self-reported their breastfeeding status. The diagnosis of PCOS was self-reported but they had to confirm diagnosis by a clinician. Perimenopause participants were diagnosed based on the Stages of Reproductive Aging Workshop (STRAW) criteria [38] and were classified as early (> 7 day differences between cycle lengths), or late (there are > 60 days of amenorrhea). Menstrual cycle monitoring with urinary hormones Participants tracked their menses, cycle length and used the Mira Monitor to test hormones in their first morning urine. Participants could use a Mira test wand that measures three hormone metabolites (E 1 3G, LH and PDG on the “Max” wand), or two test wands measuring the hormones separately (E 1 3G, LH on the “Plus” wand, and PDG on the “Confirm” wand). The wands are lateral flow assays using double antibody fluorescent labelling detected by the optical receiver in the monitor. The E 1 3G and PDG use a competition antibody assay, and the LH uses a sandwich assay (Fig. 2), previously described in detail [41]. Definition of the estimated day of ovulation (EDO) Preliminary results and pilot studies [20] have suggested that the Mira LH surge happens the day before or the day of ovulation. Based on calculations in comparison to the ClearBlue Fertility Monitor LH surge [20], which has been validated by ultrasound, the probability of ovulation occurring on the day of or day after the Mira LH surge is close to 80%. Thus the estimated day of ovulation (EDO = Day 0) used in this study was the day of the Mira LH surge. Statistical analysis Demographic, clinical and hormonal characteristics were analyzed using R software (R version 4.3.2, The R Foundation for Statistical Computing). Continuous variables (age, BMI, cycle length, follicular/luteal phase length) were described with means and standard deviations, with differences between groups calculated with ANOVA and post-hoc pairwise comparisons (p < 0.05, with post-hoc Bonferroni corrections). Discrete variables (gravida, parity) were described with median and interquartile intervals and categorical variables (ethnicity, education) were described as percentages; group differences were calculated with non-parametric Mann-Whitney U test. Missing data was excluded. The theoretical fertile window used for the statistical modeling was based on previously established criteria being 6 days up to and including the day of ovulation (EDO) [42]. Hormonal data were analyzed using additive mixed models, establishing a best fit based on smoothing splines for the hormones and random effects of individual women and individual cycles. With our sample size, we were powered to detect an effect-size of 0.5 in hormonal differences with 90% power, with alpha of 0.05, calculated with G*Power 3.1. Results Participants and Demographics An initial group of 141 women consented to be contacted for the study (Fig. 1). There were 65 participants who contributed sufficient data to be included in the study. Three of these participants withdrew their consent during the study and 5 participants were part of a chemotherapy menstrual cycle tracking group that was analyzed separately. This left a total of 57 participants contributing a total of 444 cycles of data, with an average of 11.6 days of Mira testing per cycle, summarized in Fig. 1 and Table 1 . After 6 transition cycles postpartum, there were 10 women who overlapped with other groups: 9 women had regular cycles after the postpartum transition, and 1 woman was in early perimenopause after the postpartum transition. Some of the postpartum participants (20 of the 24 in this study) were previously analyzed in more detail.[36] Breastfeeding status was available for 20 of 24 postpartum participants, 5 were partial breastfeeding and 15 were fully breastfeeding at entry in the study, but transition from full to partial breastfeeding was not tracked in detail. Of the perimenopause participants, 9 were in early perimenopause and 5 were in late perimenopause (based on STRAW criteria cycle variability, FSH was not measured). The population in this study was homogeneous (Table 1 ) - predominantly white, university educated women - not unlike previous studies of women who use hormone fertility monitors [43]. The perimenopause women were significantly older than the other 3 groups (p < 0.001). Perimenopause women had higher parity than the other 3 groups (Mann-Whitney U test p-values were all < 0.005). Women with PCOS had the lowest number of pregnancies and parity compared to all 3 groups (Table 1 ). TABLE 1 Demographic and clinical characteristics Data are mean +/- standard deviation for continuous variables (age, BMI), median (interquartile range) for discrete variables (gravida, parity), and n (%) for categorical variables (Race, Education, STRAW perimenopause criteria). BMI = body mass index. Samples for each group include overlapping numbers + n for those cycles after 6 transition cycles postpartum, e.g. 8 participants with regular cycles after 6 transition cycles postpartum. Cycle Characteristics Cycle length was significantly longer for the postpartum transition cycles than for regular cycles (p = 0.01), but the other 3 groups did not significantly differ in cycle length (Table 2 ). Follicular phase length was longer (i.e. later peak day) in postpartum transition cycles, as previously described [36], than regular cycles (p < 0.001) and perimenopause women (p = 0.001), but not significantly different from PCOS women. Luteal phase length was shorter in postpartum women than all the other groups (p < 0.001). Table 2 Cycle Parameters Characteristics Regular Cycles (n = 10 + 8) Postpartum* (n = 24) Perimenopause (n = 13 + 1) PCOS (n = 10 + 3) Cycle length 28.7 ± 3.3 a 33.1 ± 22.9 a 29.5 ± 7.3 30.5 ± 5.7 Follicular phase length 15.3 ± 3.1 b 22.4 ± 22.8 b,c 16.6 ± 6.8 c 17.8 ± 6.1 Luteal phase length 13.4 ± 1.6 d 10.6 ± 2.7 d,e,f 12.9 ± 2.8 e 12.8 ± 2.1 f Data are mean +/- standard deviation. LH , luteinizing hormone. *Postpartum cycle parameters exclude postpartum amenorrhea. Significant paired-samples differences are shown by superscript letters: a p=0.01, b p<0.001, c p=0.001, d,e,f p<0.001. Hormone Profile Modeling Hormone profiles (E 1 3G, LH and PDG) were modelled for each group with additive effects for each reproductive category and random effects per woman and per cycle (Figs. 3–6). Raw data with threshold values for each hormone on days − 5, 0 and + 5 are shown in Table 3 . In Figs. 3–5, non-overlapping standard error bands indicate a significant difference between the groups. There is a significant difference in E 1 3G levels among all reproductive categories, with women in regular cycles having higher levels overall, especially in the fertile window and the luteal phase. The perimenopause group reflected an overall hypoestrogenic state, with less of a decline in estrogen through the luteal phase than the other groups. The PCOS group also had a relatively hypoestrogenic state compared to the postpartum and regular cycles group in the follicular phase and fertile window (Fig. 3). The perimenopause group had higher LH values throughout the whole cycle, as shown in the model (Fig. 4) which made the LH surge in the model higher than the other groups, even though the raw data shows that the Postpartum group clearly has higher LH values (Table 3 ). The LH surge is concentrated in all groups around the EDO (day 0). Urinary progesterone metabolites (PDG) clearly showed the luteal phase shift. The PCOS group had the highest PDG levels, overlapping with the regular cycles group, significantly higher than both postpartum and perimenopause. The postpartum group had the lowest PDG in the model (Fig. 5) but the perimenopause group had the lowest PDG in the raw data (Table 3 ). A summary of all three hormone profiles stratified by group is shown in Fig. 6, showing the group differences described above, demonstrating the hypoestrogenic state of the PCOS and perimenopause groups and the hypoprogestogenic state of perimenopause and postpartum groups. Discussion Principal findings and results The fertile window delineated by urine hormone metabolites using the Mira monitor varies depending on a woman’s reproductive category. Women are already using these technologies on their own and will likely seek to integrate this with advice from their clinicians. With more validating studies on FemTech devices, clinicians may consider turning to evaluating personalized daily urinary hormone patterns rather than infrequent serum hormone checks that are difficult to extrapolate into the bigger picture of each menstrual cycle. In PCOS, fertile window hormonal variability is not surprising, given that there is known estradiol[30] and LH[31] abnormalities to explain the cycle irregularities. In postpartum and perimenopause transitions [35], hormone changes are present as fertility returns postpartum or wanes towards menopause. The present study demonstrated differences in the fertile window in women with perimenopause, relative to the other three groups. Our data clearly show hypoestrogenism in perimenopause, which has been well described [44], but of interest, the luteal E 1 3G plateau (Fig. 3) that we observed in perimenopause may reflect previous findings of loop-out-of-phase follicular development in the perimenopause transition [45]. Levels of LH were high across the cycle in this group (Fig. 4), with previous data showing multiple LH rises occur in this group [35]. Low luteal PDG (Fig. 5) in the perimenopause may reflect underlying abnormal luteinization processes [46]. In the postpartum group, which has been previously analyzed [35,36], higher raw LH values (Table 3 ) are likely due to a decreased sensitivity of the ovary to LH (higher values are required to trigger ovulation). In the model (Fig. 4), this was reflected in the earlier LH rise in the fertile window compared to the regular cycles and PCOS group. The postpartum group had relatively similar E 1 3G values compared to the regularly cycling group, which were higher than the PCOS and perimenopause groups for most of the cycle, reflecting their similarities in follicular E 1 3G to women in regular cycles. The PCOS group had lower overall E 1 3G and a higher luteal PDG levels, with minimal differences in LH secretion. If follicular development in women with PCOS were stimulated with medications, and it would be possible to track and individualize response to fertility treatments in PCOS using urinary hormones. The typical “textbook” menstrual cycle is the result of taking average hormone results and plotting them on a curve. An alternative to this would be individualizing assessment of the menstrual cycle by tracking urinary hormones to identify the group and individual hormonal variability [24,47–49]. Presently, applying a personalized fertile window has been left to smartphone Apps that are often inaccurate [50], or industry-developed tools that have yet to establish validity [1] or have proprietary algorithms that are not open-source. Clinicians should be aware of which tools available to patients are validated to help their patients track their menstrual cycle hormones accurately. The results of this study were not compared to the proprietary Mira algorithm used in the device’s App, but a comparison to their algorithm could be considered in the future. In the current study, we have demonstrated the importance of factoring a woman’s reproductive category (e.g. regular cycles, postpartum, PCOS, perimenopause; of course many other categories could be added to this) in delineating the fertile window, since thresholds of E 1 3G, LH and PDG were different in these four different groups (Figs. 3–6, Table 3 ). In the future, a woman’s individual hormone pattern can help to identify her own personalized fertile window that becomes more precise as more cycles are added to the predictive model. This predictive modeling is not only an educational opportunity to increase menstrual and ovulation health literacy in using these tools [51], but also a collaborative opportunity for clinicians and their patients to identify abnormalities that could help track response to treatment (e.g. for PCOS or hormone therapy in perimenopause). With a larger sample size of women with PCOS, it may have been possible to see significant differences in cycle length, later peak days and shorter luteal phases compared to women with regular cycles. Similar non-significant signals were found in perimenopause, and it is possible that perimenopause and PCOS may follow similar patterns. It should also be noted that most of our perimenopause participants were in early perimenopause, which may skew the cycle parameters which a larger sample size with more women in late perimenopause would clarify. In the future, with the use of a Mira FSH test, these hormone results may help in predicting menopause. The developers of the ClearBlue Fertility Monitor have also proposed a new FSH test for predicting menopause [52]. Strengths and limitations Our study was adequately powered to detect differences in the fertile window between the four reproductive categories, but future studies with larger sample sizes could help identify more subtle differences between the groups. The main limitation was the lack of ultrasound-confirmed ovulation, but the confirmation with a rise in urinary progesterone metabolites (PDG) effectively confirms that ovulation has occurred within the fertile window that we have defined. The sample was relatively homogenous, so future studies should focus on recruiting women with more diverse backgrounds to evaluate the role of ethnic, socioeconomic or other sources of diversity that may lead to greater personalization of the fertile window. The cost of the monitor and test wands are barriers for using these tools, but the economic benefits of urine metabolite testing at-home could lead to system-wide reduction in health care costs (e.g. with associated reduction serum hormone testing) that may lead health policy makers to consider advocating for insurance plans to cover these new testing tools just as diabetic supplies are now ubiquitously covered. Conclusions Personalization of the fertile window is not a new concept [53], but the integration of tools like urine fertility monitors with smartphone Apps[1,43] require evidence-based validation for clinicians to be confident in recommending them to patients. Validating new technology for at-home menstrual cycle monitoring should be a high priority for clinicians and health authorities to contribute to increasing menstrual health literacy and improved integration with women’s fertility goals [51]. Abbreviations CBFM: ClearBlue Fertility Monitor E 1 3G: estrone-3-glucuronide EDO: estimated day of ovulation LH: luteinizing hormone PCOS: polycystic ovarian syndrome PDG: pregnanediol glucuronide STRAW: Stages of Reproductive Aging Workshop Declarations Clinical Trial Number : Not applicable Author’s contributions (CReditT Authorship Contribution Statement) TPB (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, review & editing) RJF (Conceptualization, Formal analysis, Methodology, Supervision, Validation, Writing – original draft, review & editing) MM (Methodology, Supervision, Validation, Writing – original draft, review & editing) TS (Methodology, Validation, Writing – original draft, review & editing) LB (Data curation, Methodology, Validation, Writing – original draft, review & editing) AS (Data curation, Methodology, Validation, Writing – original draft, review & editing) KS (Data curation, Methodology, Validation, Writing – original draft, review & editing) BS (Formal analysis, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – review & editing) MS (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Writing – original draft, review & editing) Availability of data and materials Individual participant data that underlie results after deidentification could be provided to researchers to achieve aims in a methodologically sound proposal approved by an independent review committee up to 36 months after article publication. Competing interests TPB’s PhD studies are sponsored by a University of Calgary Mitacs grant co-sponsored by Quanovate Tech, developers of the Mira urine hormone fertility monitor. The remaining authors report no competing interests. Funding No funding was provided for this study. Acknowledgements The authors wish to thank the participants who contributed data for this study. References Cromack SC, Walter JR. Consumer wearables and personal devices for tracking the fertile window. Am J Obstet Gynecol. 2024; Queenan JT, Jennings VH, Hertzen H von, Spieler J. Introduction. Am J Obstet Gynecol. 1991;165(6):1977–8. May K. Home tests to monitor fertility. American Journal of Obstetrics and Gynecology. 1991 Dec 1;165(6 Pt 2):2000–2. Collins WP. The evolution of reference methods to monitor ovulation. American Journal of Obstetrics and Gynecology. 1991 Dec 1;165(6 Pt 2):1994–6. Lasley BL, Shideler SE, Munro CJ. A prototype for ovulation detection: pros and cons. American Journal of Obstetrics and Gynecology [Internet]. 1991 Dec 1;165(6 Pt 2):2003–7. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Retrieve&list_uids=1755459&dopt=abstractplus Barnard G, Karsiliyan H, Kohen F. Idiometric assay, the third way: a noncompetitive immunoassay for small molecules. American Journal of Obstetrics and Gynecology [Internet]. 1991 Dec 1;165(6 Pt 2):1997–2000. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Retrieve&list_uids=1755457&dopt=abstractplus Brown JB, Holmes J, Barker G. Use of the Home Ovarian Monitor in pregnancy avoidance. American Journal of Obstetrics and Gynecology. 1991 Dec;165(6 Pt 2):2008–11. Queenan JT, O’brien GD, Bains LM, Simpson J, Collins WP, Campbell S. Ultrasound Scanning of Ovaries to Detect Ovulation in Women**Supported by the Special Programme of Research, Development and Training in Human Reproduction, World Health Organization.††Presented at the Thirty-Sixth Annual Meeting of The American Fertility Society, March 18 to 22, 1980, Houston, Tex. Fertil Steril. 1980;34(2):99–105. Flynn AM, Docker M, Brown JB, Kennedy KI. Ultrasonographic patterns of ovarian activity during breastfeeding. American Journal of Obstetrics and Gynecology. 1991 Dec;165(6 Pt 2):2027–31. Diaz A, Laufer MR, Breech LL. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstetrics Gynecol. 2015;126(6):e143–6. Houghton LC. Menstruation as the Next Vital Sign. JAMA Netw Open. 2024;7(5):e2412778. Mu Q, Hanson L, Hoelzle J, Fehring RJ. Young Women’s Knowledge About Fertility and Their Fertility Health Risk Factors. Journal of obstetric, gynecologic, and neonatal nursing : JOGNN / NAACOG. 2019 Jan 23;48(2):153–62. Mansfield PK, Voda A, Allison G. Validating a pencil-and-paper measure of perimenopausal menstrual blood loss. Women’s Heal Issues. 2004;14(6):242–7. Ecochard R, Leiva R, Bouchard T, Boehringer H, Direito A, Mariani A, et al. Use of urinary pregnanediol 3-glucuronide to confirm ovulation. Steroids. 2013 Jul;78(10):1035–40. Bouchard TP, Fehring RJ, Schneider M. Pilot Evaluation of a New Urine Progesterone Test to Confirm Ovulation in Women Using a Fertility Monitor. Frontiers in public health. 2019 Jul 2;7:305. Li H, Gibson EA, Jukic AMZ, Baird DD, Wilcox AJ, Curry CL, et al. Menstrual cycle length variation by demographic characteristics from the Apple Women’s Health Study. npj Digit Med. 2023;6(1):100. Fehring R, Schneider M, Raviele K. Variability in the Phases of the Menstrual Cycle. Journal of Obstetric [Internet]. 2006; Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15766872558426156120 Fehring RJ, Schneider M. Variability in the hormonally estimated fertile phase of the menstrual cycle. Fertility and Sterility. 2008;90(4):1232–5. Brown JB. Types of ovarian activity in women and their significance: the Continuum (a reinterpretation of early findings). Human reproduction update. 2011;17(2):141–58. Bouchard TP, Fehring RJ, Mu Q. Quantitative Versus Qualitative Estrogen and Luteinizing Hormone Testing for Personal Fertility Monitoring. Expert Rev Mol Diagn. 2021;21(12):1349–60. Hart RJ, D’Hooghe T, Dancet EAF, Aurell R, Lunenfeld B, Orvieto R, et al. Self-Monitoring of Urinary Hormones in Combination with Telemedicine — a Timely Review and Opinion Piece in Medically Assisted Reproduction. Reprod Sci. 2022;29(11):3147–60. Nakhuda GS, Li N, Yang Z, Kang S. At-home urine estrone-3-glucuronide quantification predicts oocyte retrieval outcomes comparably with serum estradiol. F S Reports. 2023;4(1):43–8. Direito A, Bailly S, Mariani A, Ecochard R. Relationships between the luteinizing hormone surge and other characteristics of the menstrual cycle in normally ovulating women. Fertility and Sterility. 2013 Jan;99(1):279–85. Ecochard R, Bouchard T, Leiva R, Abdulla S, Dupuis O, Duterque O, et al. Characterization of hormonal profiles during the luteal phase in regularly menstruating women. Fertility and Sterility. 2017 Jul;108(1):175-182.e1. Roos J, Johnson S, Weddell S, Godehardt E, Schiffner J, Freundl G, et al. Monitoring the menstrual cycle: Comparison of urinary and serum reproductive hormones referenced to true ovulation. The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception. 2015 May 27;20(6):1–13. Hills E, Woodland MB, Divaraniya A. Using Hormone Data and Age to Pinpoint Cycle Day within the Menstrual Cycle. Medicina. 2023;59(7):1348. Pattnaik S, Das D, Venkatesan VA, Rai A. Predicting serum hormone concentration by estimation of urinary hormones through a home-use device. Hum Reproduction Open. 2022;2023(1):hoac058. Wegrzynowicz AK, Beckley A, Eyvazzadeh A, Levy G, Park J, Klein J. Complete Cycle Mapping Using a Quantitative At-Home Hormone Monitoring System in Prediction of Fertile Days, Confirmation of Ovulation, and Screening for Ovulation Issues Preventing Conception. Medicina. 2022;58(12):1853. Wang R, Mol BWJ. The Rotterdam criteria for polycystic ovary syndrome: evidence-based criteria? Hum Reprod. 2016;32(2):261–4. Chauvin S, Cohen-Tannoudji J, Guigon CJ. Estradiol Signaling at the Heart of Folliculogenesis: Its Potential Deregulation in Human Ovarian Pathologies. Int J Mol Sci. 2022;23(1):512. Arroyo A, Laughlin GA, Morales AJ, Yen SSC. Inappropriate Gonadotropin Secretion in Polycystic Ovary Syndrome: Influence of Adiposity1. J Clin Endocrinol Metab. 1997;82(11):3728–33. Bouchard T, Blackwell L, Brown S, Fehring R, Parenteau-Carreau S. Dissociation between Cervical Mucus and Urinary Hormones during the Postpartum Return of Fertility in Breastfeeding Women: The Linacre Quarterly. 2018 Nov 30;85(4):399–411. Schneider MM, Fehring RJ, Bouchard TP. Effectiveness of a Postpartum Breastfeeding Protocol for Avoiding Pregnancy. Linacre Q. 2023 Jul 27;002436392311672. Fehring R, Barron M, Schneider M. Protocol for determining fertility while breastfeeding and not in cycles. Fertility and Sterility [Internet]. 2005;84(3):805–7. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16366404905934012477 Bouchard TP, Doyle-Baker PK, Yong PJ, Fehring RJ, Schneider M. Validating At-Home Urinary Hormone Measurements in Postpartum and Perimenopause Fertility Transitions. Women’s Health Reports. 2024;(in press). Bouchard TP, Schweinsberg K, Smith A, Schneider M. Using Quantitative Hormone Monitoring to Identify the Postpartum Return of Fertility. Medicina. 2023;59(11):2008. Khoudary SRE, Greendale G, Crawford SL, Avis NE, Brooks MM, Thurston RC, et al. The menopause transition and women’s health at midlife: a progress report from the Study of Women’s Health Across the Nation (SWAN). Menopause (N York, Ny). 2019;26(10):1213–27. Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10. Menopause. 2012;19(4):387–95. Meyers M, Fehring RJ, Schneider M. Case Reports from Women Using a Quantitative Hormone Monitor to Track the Perimenopause Transition. Medicina. 2023;59(10):1743. Munro MG, Critchley HOD, Fraser IS. The FIGO systems for nomenclature and classification of causes of abnormal uterine bleeding in the reproductive years: who needs them? American Journal of Obstetrics and Gynecology. 2012 Oct;207(4):259–65. Bouchard T, Yong P, Doyle-Baker P. Establishing a Gold Standard for Quantitative Menstrual Cycle Monitoring. Medicina. 2023 Aug 24;59(9):1513. Dunson DB, Baird DD, Wilcox AJ, Weinberg CR. Day-specific probabilities of clinical pregnancy based on two studies with imperfect measures of ovulation. Hum Reprod. 1999;14(7):1835–9. Stujenske TM, Mu Q, Capotosto MP, Bouchard TP. Survey Analysis of Quantitative and Qualitative Menstrual Cycle Tracking Technologies. Medicina. 2023 Aug 22;59(9):1509. Turner RJ, Kerber IJ. A theory of eu-estrogenemia. Menopause. 2017;24(9):1086–97. Hale GE, Hughes CL, Burger HG, Robertson DM, Fraser IS. Atypical estradiol secretion and ovulation patterns caused by luteal out-of-phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopausal transition. Menopause. 2009;16(1):50–9. O’Connor KA, Ferrell R, Brindle E, Trumble B, Shofer J, Holman DJ, et al. Progesterone and ovulation across stages of the transition to menopause. Menopause. 2009;16(6):1178–87. Ecochard R, Guillerm A, Leiva R, Bouchard T, Direito A, Boehringer H. Characterization of follicle stimulating hormone profiles in normal ovulating women. Fertil Steril. 2014;102(1):237-243.e5. Abdullah S, Bouchard T, Leiva R, Boehringer H, Iwaz J, Ecochard R. Distinct urinary progesterone metabolite profiles during the luteal phase. Hormone Mol Biology Clin Investigation. 2022;0(0). Johnson S, Weddell S, Godbert S, Freundl G, Roos J, Gnoth C. Development of the first urinary reproductive hormone ranges referenced to independently determined ovulation day. Clinical chemistry and laboratory medicine : CCLM / FESCC. 2015 Jan 17;0(0):1099–108. Zwingerman R, Chaikof M, Jones C. A Critical Appraisal of Fertility and Menstrual Tracking Apps for the iPhone. J Obstetrics Gynaecol Can. 2020;42(5):583–90. Yong PJ, Khan Z, Wahl K, Bouchard TP, Doyle-Baker PK, Prior JC. Menstrual Health Literacy, Equity and Research Priorities. J Obstetrics Gynaecol Can. 2024;(in press). Clearblue Menopause Stage Indicator [Internet]. [cited 2024 Dec 12]. Available from: https://www.clearblue.com/healthcare-professionals/menopause/stage-indicator Djerassi C. Fertility awareness: jet-age rhythm method? Science. 1990;248:1061–2. Table 3 Table 3 is available in the Supplementary Files section. Additional Declarations Competing interest reported. TPB’s PhD studies are sponsored by a University of Calgary Mitacs grant co-sponsored by Quanovate Tech, developers of the Mira urine hormone fertility monitor. The remaining authors report no competing interests. Supplementary Files TABLE3.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 Aug, 2025 Reviews received at journal 03 Jul, 2025 Reviews received at journal 22 Jun, 2025 Reviewers agreed at journal 08 Jun, 2025 Reviewers agreed at journal 01 Jun, 2025 Reviewers invited by journal 01 Jun, 2025 Editor assigned by journal 21 May, 2025 Submission checks completed at journal 21 May, 2025 First submitted to journal 15 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6669318","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":465086201,"identity":"9a78afce-c16a-4c7a-b29a-38675f1ceda5","order_by":0,"name":"Thomas P. Bouchard","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYDACCSBmbGBg4AdxHhCjgwemRRKIGRJI0mJwgFgt9tLNxyR+7rDLN76R/PBDwi+7fIMDzA8/4LVF5liaZO+ZZMttN9KMJRL7ki03HGAzlsDvsBwzacY2ZgOzGzkMEok9zAYGB3gYiNFSb2A8I4f5R2JPPUgL8w8itBw2MJDIYZNI+HEYpIUNvy13jiVb9rYdN5A488zMIrHhuIHkYTYzC3xa2Gc3H7zxs63agL89+fGND3+qDfiONz++gU8LKmBsY2BQOEy8ehD4w8Ag30CallEwCkbBKBj+AADkzUf6ekM/gAAAAABJRU5ErkJggg==","orcid":"","institution":"University of Calgary","correspondingAuthor":true,"prefix":"","firstName":"Thomas","middleName":"P.","lastName":"Bouchard","suffix":""},{"id":465086202,"identity":"aba5f4ac-7711-40be-9386-9b31c3c75763","order_by":1,"name":"Richard J. Fehring","email":"","orcid":"","institution":"Marquette University","correspondingAuthor":false,"prefix":"","firstName":"Richard","middleName":"J.","lastName":"Fehring","suffix":""},{"id":465086204,"identity":"d159378b-4209-4f6b-b7fc-5e3ae88eabcc","order_by":2,"name":"Maria Meyers","email":"","orcid":"","institution":"Marquette Method Profess","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Meyers","suffix":""},{"id":465086205,"identity":"5e23039c-664d-4412-9d37-7d524ae90da1","order_by":3,"name":"Theresa Stujenske","email":"","orcid":"","institution":"Duquesne University","correspondingAuthor":false,"prefix":"","firstName":"Theresa","middleName":"","lastName":"Stujenske","suffix":""},{"id":465086206,"identity":"462fbc80-15f0-43b2-b453-8338e73f8e8e","order_by":4,"name":"Louise Boychuk","email":"","orcid":"","institution":"Marquette Method Profess","correspondingAuthor":false,"prefix":"","firstName":"Louise","middleName":"","lastName":"Boychuk","suffix":""},{"id":465086211,"identity":"91c061af-f4d2-48d7-aca0-d7a9fabf06d0","order_by":5,"name":"Amanda Smith","email":"","orcid":"","institution":"Marquette Method Profess","correspondingAuthor":false,"prefix":"","firstName":"Amanda","middleName":"","lastName":"Smith","suffix":""},{"id":465086213,"identity":"bbb18c53-6d44-4180-84d3-d60d5913e6b4","order_by":6,"name":"Katherine Schweinsberg","email":"","orcid":"","institution":"Marquette Method Profess","correspondingAuthor":false,"prefix":"","firstName":"Katherine","middleName":"","lastName":"Schweinsberg","suffix":""},{"id":465086214,"identity":"8b88d673-886b-4912-9b38-63a3392b5050","order_by":7,"name":"Bruno Scarpa","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Bruno","middleName":"","lastName":"Scarpa","suffix":""},{"id":465086215,"identity":"205c796c-b05f-496b-b721-c23ad5532e05","order_by":8,"name":"Mary Schneider","email":"","orcid":"","institution":"Marquette University","correspondingAuthor":false,"prefix":"","firstName":"Mary","middleName":"","lastName":"Schneider","suffix":""}],"badges":[],"createdAt":"2025-05-15 06:23:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6669318/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6669318/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83840967,"identity":"dcf92857-20f6-4ba9-aca5-3f7c950a3c33","added_by":"auto","created_at":"2025-06-03 14:10:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":697943,"visible":true,"origin":"","legend":"\u003cp\u003eConsort Flow Diagram. Consort describing outlining initial enrollment, allocation to four groups, attrition (follow-up) and final analysis (n=57) with the breakdown of different groups. For women beyond 6 cycles postpartum, they were allocated into regular cycles (n=8), perimenopause (n=1) and PCOS (n=3).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6669318/v1/d7f3f7a7c54cee83cdecb37a.jpg"},{"id":83841232,"identity":"80ff6c19-43ba-47b8-bea2-7c6361deb669","added_by":"auto","created_at":"2025-06-03 14:18:44","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":371964,"visible":true,"origin":"","legend":"\u003cp\u003eMira Monitor testing and lateral flow assay. (A) Mira test stick dipped into first morning urine cup. (B) Insertion of test stick into the Mira monitor with optical analyzer. (C) Lateral flow assay view inside test stick with absorbent end on right and urine sampling end on left. The lateral flow assay is described based on hormone binding for sandwich and competition assays and how these affect line intensity.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6669318/v1/790c717e5c9fa191ce4c463c.jpg"},{"id":83841231,"identity":"6ce7b5d3-f20f-4e3f-8476-25a7c9773396","added_by":"auto","created_at":"2025-06-03 14:18:44","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":298216,"visible":true,"origin":"","legend":"\u003cp\u003eE\u003csub\u003e1\u003c/sub\u003e3G hormone levels stratified by reproductive category.\u003cstrong\u003e \u003c/strong\u003eEstrone-3-glucuronide (E\u003csub\u003e1\u003c/sub\u003e3G) hormone values (ng/mL) plotted against the estimated day of ovulation (EDO, EDO=0 is the day of the Mira LH surge), with four curves based on the four groups shown in the legend (regular cycles, perimenopause, PCOS, postpartum). The fertile window is delineated by the two grey bars from days -5 to +1 relative to the EDO. The follicular and luteal phases are marked in bands (negative days are the follicular phase and positive days are the luteal phase).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6669318/v1/7669b6582bd8646ce559b4f4.jpg"},{"id":83842036,"identity":"0ca8e987-326f-4e94-b571-c2446de11b5e","added_by":"auto","created_at":"2025-06-03 14:26:45","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":167718,"visible":true,"origin":"","legend":"\u003cp\u003eLH hormone levels stratified by reproductive category.\u003cstrong\u003e \u003c/strong\u003eLuteinizing hormone (LH) hormone values (mIU/mL) plotted against the estimated day of ovulation (EDO, EDO=0 is the day of the Mira LH surge), with four curves based on the four groups shown in the legend (regular cycles, perimenopause, PCOS, postpartum). The fertile window is delineated by the two grey bars from days -5 to +1 relative to the EDO. The follicular and luteal phases are marked in bands (negative days are the follicular phase and positive days are the luteal phase).\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6669318/v1/db8ffa887a6cf9db089d0ccf.jpg"},{"id":83842100,"identity":"9216bc96-95d6-48b0-b2e2-ac023e31cd68","added_by":"auto","created_at":"2025-06-03 14:34:45","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":249289,"visible":true,"origin":"","legend":"\u003cp\u003ePDG hormone levels stratified by reproductive category. Pregnanediol glucuronide (PDG) hormone values (ug/mL) plotted against the estimated day of ovulation (EDO, EDO=0 is the day of the Mira LH surge), with four curves based on the four groups shown in the legend (regular cycles, perimenopause, PCOS, postpartum). The fertile window is delineated by the two grey bars from days -5 to +1 relative to the EDO. The follicular and luteal phases are marked in bands (negative days are the follicular phase and positive days are the luteal phase).\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6669318/v1/4d8a081fcc63f2564cfdcf44.jpg"},{"id":83842099,"identity":"2efba7dd-8c66-48c4-8e09-1c2297ac42a0","added_by":"auto","created_at":"2025-06-03 14:34:45","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":503615,"visible":true,"origin":"","legend":"\u003cp\u003eHormone profiles by reproductive category. All three hormones (E\u003csub\u003e1\u003c/sub\u003e3G, LH and PDG) are plotted against the estimated day of ovulation (EDO, EDO=0 is the day of the Mira LH surge), separated for each of the four groups (A) regular cycles, (B) perimenopause, (C) PCOS, (D) postpartum. The fertile window is delineated by the two grey bars from days -5 to +1 relative to the EDO. The follicular and luteal phases are marked in bands (negative days are the follicular phase and positive days are the luteal phase).\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6669318/v1/3b94646aa61a8daed12eb619.jpg"},{"id":83844021,"identity":"751ef09a-f0c3-4804-abb1-bab0d11d3247","added_by":"auto","created_at":"2025-06-03 14:42:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3061991,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6669318/v1/41328a9d-3165-49b6-adc6-e45e75712952.pdf"},{"id":83840947,"identity":"79d6d8eb-9729-4034-af8c-2dd7726c4d05","added_by":"auto","created_at":"2025-06-03 14:10:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":48224,"visible":true,"origin":"","legend":"","description":"","filename":"TABLE3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6669318/v1/633c956688891679dc4cf357.docx"}],"financialInterests":"Competing interest reported. TPB’s PhD studies are sponsored by a University of Calgary Mitacs grant co-sponsored by Quanovate Tech, developers of the Mira urine hormone fertility monitor. The remaining authors report no competing interests.","formattedTitle":"Modeling Fertile Window Differences Across the Reproductive Lifespan with Quantitative Urine Hormone Monitoring of the Menstrual Cycle","fulltext":[{"header":"Background","content":"\u003cp\u003eIn a recent clinical opinion article [1], Cromack and Walter described the rapidly expanding Femtech industry with a focus on wearables and personal devices to identify the fertile window. Marketing and use of these devices for menstrual cycle monitoring is outpacing evidence-based validation studies [1]. Of historic interest, the same climate of change was present over three decades ago at a conference sponsored by the World Health Organization [2]. Multiple studies presented the use of at-home tests to track the fertile window [3\u0026ndash;6], including a new urine fertility monitor to avoid pregnancy[7]. By that time, ultrasound studies had already been published outlining criteria for the detection of ovulation [8], and at this conference Flynn[9] described ovulation on ultrasound in breastfeeding women. The current study recapitulates this early work defining the fertile window and ovulation in various reproductive circumstances with an emphasis on the menstrual cycle as a vital sign for women\u0026rsquo;s health [10\u0026ndash;12]. However, a vital sign requires having validation, for example, valid tools to track bleeding [13], ovulation [1], and confirmation of whether ovulation has occurred [14,15]. This vital sign needs to take into account variability in cycle length[16] and phases of the menstrual cycle in various reproductive circumstances, not just regularly cycling women [17,18]. Monitoring the menstrual cycle parameters in postpartum and perimenopause women as well as those with polycystic ovarian syndrome (PCOS) using the new Mira fertility monitor was the aim of the present study, to understand the variability in hormones across the continuum of the menstrual cycle [19].\u003c/p\u003e \u003cp\u003eThe Mira monitor measures the urinary metabolites of follicle-stimulating hormone (FSH), of estradiol in the form of estrone-3-glucuronide (E\u003csub\u003e1\u003c/sub\u003e3G), of luteinizing hormone (LH), and of progesterone in the form of pregnanediol glucuronide (PDG) previously described in detail [20]. Urine hormone monitoring provides a non-invasive means of assessing underlying ovulatory function and menstrual cycle physiology[21] and Mira E\u003csub\u003e1\u003c/sub\u003e3G has been compared to serum estradiol in a recent study [22]. In the follicular phase of the menstrual cycle, rising levels of estrogen from the dominant follicle trigger a surge of luteinizing hormone from the anterior pituitary gland. This LH surge typically occurs 24\u0026ndash;48 hours before ovulation, leading to the release of a mature egg [23]. Following ovulation, the luteinized follicle (corpus luteum) produces progesterone, which is essential for preparing the endometrium for potential implantation [24]. Urine and serum reproductive hormone measurements demonstrate strong agreement [25], but unlike serum testing, which provides a measure of reproductive hormone levels at a single time point, daily first morning urine hormone testing enables a real-time analysis of hormone levels across the entire menstrual cycle. This could refine our understanding of menstrual cycle parameters, including follicular and luteal phase length, the fertile window, and timing of ovulation [20,26\u0026ndash;28]. The Mira monitor was chosen for the current study based on pilot data demonstrating good acceptability and ease of use by participants [20].\u003c/p\u003e \u003cp\u003eTracking the fertile window is challenging in women with polycystic ovarian syndrome (PCOS). The diagnosis of PCOS is based on meeting two of the following three consensus-based Rotterdarm criteria [29]: irregular cycles, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound. With the cycle irregularities of PCOS, related to estradiol dysregulation [30] and abnormal gonadotropin LH secretion [31], the Mira monitor has the potential to provide clarity to women with PCOS regarding their hormone patterns by identifying whether an LH rise is appropriately followed by a progesterone rise suggesting corpus luteum formation. It may also provide a way to track pre- and post-treatment interventions for PCOS.\u003c/p\u003e \u003cp\u003eAnother challenging time to navigate the menstrual cycle is during postpartum amenorrhea and the first few transition cycles that are longer than usual [32]. The ClearBlue Fertility Monitor (CBFM) has been used in combination with the Marquette Method of family planning to track the return of fertility postpartum [33,34], but does not provide quantitative hormone data so may incorrectly identify the day of ovulation [35]. Using the Mira monitor to track E\u003csub\u003e1\u003c/sub\u003e3G, LH and PDG can help to identify which rises in E\u003csub\u003e1\u003c/sub\u003e3G and LH may potentially be ovulatory, with rising PDG to confirm the first ovulation postpartum. This would inform the postpartum return of fertility [36].\u003c/p\u003e \u003cp\u003eFinally, the perimenopause transition also presents difficulties related to irregular cycles, variable hormonal patterns and disturbing vasomotor symptoms due to these hormonal changes [37]. This transition has been categorized in detail based on the Stages of Reproductive Aging Workshop (STRAW) in 2012 [38]. Instead of using a woman\u0026rsquo;s age as a marker for infertility, this system takes into account cycle length variability to describe reproductive stage and fertility. However, rather than just identifying cycle length variability, the Mira monitor may help to better delineate the hormonal transition as proposed in a recent case series [39].\u003c/p\u003e \u003cp\u003eIn the current study, quantitative urine hormones (E\u003csub\u003e1\u003c/sub\u003e3G, LH and PDG; due to insufficient FSH data, FSH was not included), referenced to the LH surge day (the estimated day of ovulation) and confirmed by a rise in PDG, were compared between four reproductive categories to outline group differences in hormones during the fertile window and phases of the menstrual cycle.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eAim, Design and Setting\u003c/h2\u003e\n \u003cp\u003eThis was an observational cohort study with prospective data collection using the Mira Monitor in various circumstances, with ethical approval by the Marquette University research ethics board (HR 4276, April 4, 2023) in accordance with the Declaration of Helsinki. Inclusion criteria were: (1) English-speaking women between the ages of 18 and 52, (2) using their own Mira monitor and test wands, in (3) the four reproductive categories (regular cycles, PCOS, postpartum and perimenopause). Women were excluded if they: (1) were on hormonal medications that would impact ovulation, (2) had a previous hysterectomy or oophorectomy. All participants provided informed consent to participate.\u003c/p\u003e\n \u003cp\u003eRecruitment was initiated via email to Marquette Method health care providers who teach women how to monitor their menstrual cycles. Eligible participants were asked to email the principal investigator (MS), who sent them a description of the study and links to complete: a consent form, a demographics form, and a chart data form. Participants consented to share their hormone data from an online Mira portal for health care providers. Forms and chart data were uploaded to a secure, private Marquette University OneDrive folder. Data was collected over 1 year, after which access to the portal was discontinued.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eDefinitions of reproductive categories\u003c/h3\u003e\n\u003cp\u003eThe definition of regular cycles was based on previously established criteria,[40] with consistent cycles (\u0026le;\u0026thinsp;7 days variation between cycles) that were 24\u0026ndash;38 days in length. Postpartum women were defined as being within delivery of a child in the last year and within the first 6 transition cycles postpartum after the initial postpartum amenorrhea, they self-reported their breastfeeding status. The diagnosis of PCOS was self-reported but they had to confirm diagnosis by a clinician. Perimenopause participants were diagnosed based on the Stages of Reproductive Aging Workshop (STRAW) criteria [38] and were classified as early (\u0026gt;\u0026thinsp;7 day differences between cycle lengths), or late (there are \u0026gt;\u0026thinsp;60 days of amenorrhea).\u003c/p\u003e\n\u003ch3\u003eMenstrual cycle monitoring with urinary hormones\u003c/h3\u003e\n\u003cp\u003eParticipants tracked their menses, cycle length and used the Mira Monitor to test hormones in their first morning urine. Participants could use a Mira test wand that measures three hormone metabolites (E\u003csub\u003e1\u003c/sub\u003e3G, LH and PDG on the \u0026ldquo;Max\u0026rdquo; wand), or two test wands measuring the hormones separately (E\u003csub\u003e1\u003c/sub\u003e3G, LH on the \u0026ldquo;Plus\u0026rdquo; wand, and PDG on the \u0026ldquo;Confirm\u0026rdquo; wand). The wands are lateral flow assays using double antibody fluorescent labelling detected by the optical receiver in the monitor. The E\u003csub\u003e1\u003c/sub\u003e3G and PDG use a competition antibody assay, and the LH uses a sandwich assay (Fig. 2), previously described in detail [41].\u003c/p\u003e\n\u003ch3\u003eDefinition of the estimated day of ovulation (EDO)\u003c/h3\u003e\n\u003cp\u003ePreliminary results and pilot studies [20] have suggested that the Mira LH surge happens the day before or the day of ovulation. Based on calculations in comparison to the ClearBlue Fertility Monitor LH surge [20], which has been validated by ultrasound, the probability of ovulation occurring on the day of or day after the Mira LH surge is close to 80%. Thus the estimated day of ovulation (EDO\u0026thinsp;=\u0026thinsp;Day 0) used in this study was the day of the Mira LH surge.\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eDemographic, clinical and hormonal characteristics were analyzed using R software (R version 4.3.2, The R Foundation for Statistical Computing). Continuous variables (age, BMI, cycle length, follicular/luteal phase length) were described with means and standard deviations, with differences between groups calculated with ANOVA and post-hoc pairwise comparisons (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, with post-hoc Bonferroni corrections). Discrete variables (gravida, parity) were described with median and interquartile intervals and categorical variables (ethnicity, education) were described as percentages; group differences were calculated with non-parametric Mann-Whitney U test. Missing data was excluded.\u003c/p\u003e\n \u003cp\u003eThe theoretical fertile window used for the statistical modeling was based on previously established criteria being 6 days up to and including the day of ovulation (EDO) [42]. Hormonal data were analyzed using additive mixed models, establishing a best fit based on smoothing splines for the hormones and random effects of individual women and individual cycles.\u003c/p\u003e\n \u003cp\u003eWith our sample size, we were powered to detect an effect-size of 0.5 in hormonal differences with 90% power, with alpha of 0.05, calculated with G*Power 3.1.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eParticipants and Demographics\u003c/h2\u003e\n \u003cp\u003eAn initial group of 141 women consented to be contacted for the study (Fig. 1). There were 65 participants who contributed sufficient data to be included in the study. Three of these participants withdrew their consent during the study and 5 participants were part of a chemotherapy menstrual cycle tracking group that was analyzed separately. This left a total of 57 participants contributing a total of 444 cycles of data, with an average of 11.6 days of Mira testing per cycle, summarized in Fig. 1 and Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. After 6 transition cycles postpartum, there were 10 women who overlapped with other groups: 9 women had regular cycles after the postpartum transition, and 1 woman was in early perimenopause after the postpartum transition. Some of the postpartum participants (20 of the 24 in this study) were previously analyzed in more detail.[36] Breastfeeding status was available for 20 of 24 postpartum participants, 5 were partial breastfeeding and 15 were fully breastfeeding at entry in the study, but transition from full to partial breastfeeding was not tracked in detail. Of the perimenopause participants, 9 were in early perimenopause and 5 were in late perimenopause (based on STRAW criteria cycle variability, FSH was not measured).\u003c/p\u003e\n \u003cp\u003eThe population in this study was homogeneous (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) - predominantly white, university educated women - not unlike previous studies of women who use hormone fertility monitors [43]. The perimenopause women were significantly older than the other 3 groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Perimenopause women had higher parity than the other 3 groups (Mann-Whitney U test p-values were all \u0026lt;\u0026thinsp;0.005). Women with PCOS had the lowest number of pregnancies and parity compared to all 3 groups (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTABLE 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDemographic and clinical characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cimg 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\"\u003e\u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003eData are mean +/- standard deviation for continuous variables (age, BMI), median (interquartile range) for discrete variables (gravida, parity), and n (%) for categorical variables (Race, Education, STRAW perimenopause criteria). \u003cem\u003eBMI\u003c/em\u003e\u0026thinsp;=\u0026thinsp;body mass index. Samples for each group include overlapping numbers\u0026thinsp;+\u0026thinsp;n for those cycles after 6 transition cycles postpartum, e.g. 8 participants with regular cycles after 6 transition cycles postpartum.\u003c/div\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eCycle Characteristics\u003c/h2\u003e\n \u003cp\u003eCycle length was significantly longer for the postpartum transition cycles than for regular cycles (p\u0026thinsp;=\u0026thinsp;0.01), but the other 3 groups did not significantly differ in cycle length (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Follicular phase length was longer (i.e. later peak day) in postpartum transition cycles, as previously described [36], than regular cycles (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and perimenopause women (p\u0026thinsp;=\u0026thinsp;0.001), but not significantly different from PCOS women. Luteal phase length was shorter in postpartum women than all the other groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCycle Parameters\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRegular Cycles (n\u0026thinsp;=\u0026thinsp;10\u0026thinsp;+\u0026thinsp;8)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePostpartum*\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePerimenopause (n\u0026thinsp;=\u0026thinsp;13\u0026thinsp;+\u0026thinsp;1)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePCOS\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10\u0026thinsp;+\u0026thinsp;3)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCycle length\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.1\u0026thinsp;\u0026plusmn;\u0026thinsp;22.9\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFollicular phase length\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.4\u0026thinsp;\u0026plusmn;\u0026thinsp;22.8\u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLuteal phase length\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003csup\u003ed,e,f\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eData are mean +/- standard deviation. \u003cem\u003eLH\u003c/em\u003e, luteinizing hormone. *Postpartum cycle parameters exclude postpartum amenorrhea. Significant paired-samples differences are shown by superscript letters: \u003csup\u003ea\u003c/sup\u003ep=0.01, \u003csup\u003eb\u003c/sup\u003ep\u0026lt;0.001, \u003csup\u003ec\u003c/sup\u003ep=0.001, \u003csup\u003ed,e,f\u003c/sup\u003ep\u0026lt;0.001.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eHormone Profile Modeling\u003c/h2\u003e\n \u003cp\u003eHormone profiles (E\u003csub\u003e1\u003c/sub\u003e3G, LH and PDG) were modelled for each group with additive effects for each reproductive category and random effects per woman and per cycle (Figs. 3\u0026ndash;6). Raw data with threshold values for each hormone on days \u0026minus;\u0026thinsp;5, 0 and +\u0026thinsp;5 are shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. In Figs.\u0026nbsp;3\u0026ndash;5, non-overlapping standard error bands indicate a significant difference between the groups.\u003c/p\u003e\n \u003cp\u003eThere is a significant difference in E\u003csub\u003e1\u003c/sub\u003e3G levels among all reproductive categories, with women in regular cycles having higher levels overall, especially in the fertile window and the luteal phase. The perimenopause group reflected an overall hypoestrogenic state, with less of a decline in estrogen through the luteal phase than the other groups. The PCOS group also had a relatively hypoestrogenic state compared to the postpartum and regular cycles group in the follicular phase and fertile window (Fig.\u0026nbsp;3).\u003c/p\u003e\n \u003cp\u003eThe perimenopause group had higher LH values throughout the whole cycle, as shown in the model (Fig. 4) which made the LH surge in the model higher than the other groups, even though the raw data shows that the Postpartum group clearly has higher LH values (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The LH surge is concentrated in all groups around the EDO (day 0).\u003c/p\u003e\n \u003cp\u003eUrinary progesterone metabolites (PDG) clearly showed the luteal phase shift. The PCOS group had the highest PDG levels, overlapping with the regular cycles group, significantly higher than both postpartum and perimenopause. The postpartum group had the lowest PDG in the model (Fig. 5) but the perimenopause group had the lowest PDG in the raw data (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eA summary of all three hormone profiles stratified by group is shown in Fig. 6, showing the group differences described above, demonstrating the hypoestrogenic state of the PCOS and perimenopause groups and the hypoprogestogenic state of perimenopause and postpartum groups.\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePrincipal findings and results\u003c/h2\u003e \u003cp\u003eThe fertile window delineated by urine hormone metabolites using the Mira monitor varies depending on a woman\u0026rsquo;s reproductive category. Women are already using these technologies on their own and will likely seek to integrate this with advice from their clinicians. With more validating studies on FemTech devices, clinicians may consider turning to evaluating personalized daily urinary hormone patterns rather than infrequent serum hormone checks that are difficult to extrapolate into the bigger picture of each menstrual cycle.\u003c/p\u003e \u003cp\u003eIn PCOS, fertile window hormonal variability is not surprising, given that there is known estradiol[30] and LH[31] abnormalities to explain the cycle irregularities. In postpartum and perimenopause transitions [35], hormone changes are present as fertility returns postpartum or wanes towards menopause. The present study demonstrated differences in the fertile window in women with perimenopause, relative to the other three groups. Our data clearly show hypoestrogenism in perimenopause, which has been well described [44], but of interest, the luteal E\u003csub\u003e1\u003c/sub\u003e3G plateau (Fig.\u0026nbsp;3) that we observed in perimenopause may reflect previous findings of loop-out-of-phase follicular development in the perimenopause transition [45]. Levels of LH were high across the cycle in this group (Fig.\u0026nbsp;4), with previous data showing multiple LH rises occur in this group [35]. Low luteal PDG (Fig.\u0026nbsp;5) in the perimenopause may reflect underlying abnormal luteinization processes [46].\u003c/p\u003e \u003cp\u003eIn the postpartum group, which has been previously analyzed [35,36], higher raw LH values (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) are likely due to a decreased sensitivity of the ovary to LH (higher values are required to trigger ovulation). In the model (Fig.\u0026nbsp;4), this was reflected in the earlier LH rise in the fertile window compared to the regular cycles and PCOS group. The postpartum group had relatively similar E\u003csub\u003e1\u003c/sub\u003e3G values compared to the regularly cycling group, which were higher than the PCOS and perimenopause groups for most of the cycle, reflecting their similarities in follicular E\u003csub\u003e1\u003c/sub\u003e3G to women in regular cycles.\u003c/p\u003e \u003cp\u003eThe PCOS group had lower overall E\u003csub\u003e1\u003c/sub\u003e3G and a higher luteal PDG levels, with minimal differences in LH secretion. If follicular development in women with PCOS were stimulated with medications, and it would be possible to track and individualize response to fertility treatments in PCOS using urinary hormones.\u003c/p\u003e \u003cp\u003eThe typical \u0026ldquo;textbook\u0026rdquo; menstrual cycle is the result of taking average hormone results and plotting them on a curve. An alternative to this would be individualizing assessment of the menstrual cycle by tracking urinary hormones to identify the group and individual hormonal variability [24,47\u0026ndash;49]. Presently, applying a personalized fertile window has been left to smartphone Apps that are often inaccurate [50], or industry-developed tools that have yet to establish validity [1] or have proprietary algorithms that are not open-source. Clinicians should be aware of which tools available to patients are validated to help their patients track their menstrual cycle hormones accurately. The results of this study were not compared to the proprietary Mira algorithm used in the device\u0026rsquo;s App, but a comparison to their algorithm could be considered in the future.\u003c/p\u003e \u003cp\u003eIn the current study, we have demonstrated the importance of factoring a woman\u0026rsquo;s reproductive category (e.g. regular cycles, postpartum, PCOS, perimenopause; of course many other categories could be added to this) in delineating the fertile window, since thresholds of E\u003csub\u003e1\u003c/sub\u003e3G, LH and PDG were different in these four different groups (Figs.\u0026nbsp;3\u0026ndash;6, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In the future, a woman\u0026rsquo;s individual hormone pattern can help to identify her own personalized fertile window that becomes more precise as more cycles are added to the predictive model. This predictive modeling is not only an educational opportunity to increase menstrual and ovulation health literacy in using these tools [51], but also a collaborative opportunity for clinicians and their patients to identify abnormalities that could help track response to treatment (e.g. for PCOS or hormone therapy in perimenopause).\u003c/p\u003e \u003cp\u003eWith a larger sample size of women with PCOS, it may have been possible to see significant differences in cycle length, later peak days and shorter luteal phases compared to women with regular cycles. Similar non-significant signals were found in perimenopause, and it is possible that perimenopause and PCOS may follow similar patterns. It should also be noted that most of our perimenopause participants were in early perimenopause, which may skew the cycle parameters which a larger sample size with more women in late perimenopause would clarify. In the future, with the use of a Mira FSH test, these hormone results may help in predicting menopause. The developers of the ClearBlue Fertility Monitor have also proposed a new FSH test for predicting menopause [52].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eOur study was adequately powered to detect differences in the fertile window between the four reproductive categories, but future studies with larger sample sizes could help identify more subtle differences between the groups. The main limitation was the lack of ultrasound-confirmed ovulation, but the confirmation with a rise in urinary progesterone metabolites (PDG) effectively confirms that ovulation has occurred within the fertile window that we have defined. The sample was relatively homogenous, so future studies should focus on recruiting women with more diverse backgrounds to evaluate the role of ethnic, socioeconomic or other sources of diversity that may lead to greater personalization of the fertile window. The cost of the monitor and test wands are barriers for using these tools, but the economic benefits of urine metabolite testing at-home could lead to system-wide reduction in health care costs (e.g. with associated reduction serum hormone testing) that may lead health policy makers to consider advocating for insurance plans to cover these new testing tools just as diabetic supplies are now ubiquitously covered.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePersonalization of the fertile window is not a new concept [53], but the integration of tools like urine fertility monitors with smartphone Apps[1,43] require evidence-based validation for clinicians to be confident in recommending them to patients. Validating new technology for at-home menstrual cycle monitoring should be a high priority for clinicians and health authorities to contribute to increasing menstrual health literacy and improved integration with women\u0026rsquo;s fertility goals [51].\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCBFM: ClearBlue Fertility Monitor\u003c/p\u003e\n\u003cp\u003eE\u003csub\u003e1\u003c/sub\u003e3G: estrone-3-glucuronide\u003c/p\u003e\n\u003cp\u003eEDO: estimated day of ovulation\u003c/p\u003e\n\u003cp\u003eLH: luteinizing hormone\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePCOS: polycystic ovarian syndrome\u003c/p\u003e\n\u003cp\u003ePDG: pregnanediol glucuronide\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSTRAW: Stages of Reproductive Aging Workshop\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e: Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor\u0026rsquo;s contributions (CReditT Authorship Contribution Statement)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTPB (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing \u0026ndash; original draft, review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003eRJF (Conceptualization, Formal analysis, Methodology, Supervision, Validation, Writing \u0026ndash; original draft, review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003eMM (Methodology, Supervision, Validation, Writing \u0026ndash; original draft, review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003eTS (Methodology, Validation, Writing \u0026ndash; original draft, review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003eLB (Data curation, Methodology, Validation, Writing \u0026ndash; original draft, review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003eAS (Data curation, Methodology, Validation, Writing \u0026ndash; original draft, review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003eKS (Data curation, Methodology, Validation, Writing \u0026ndash; original draft, review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003eBS (Formal analysis, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing \u0026ndash; review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003eMS (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Writing \u0026ndash; original draft, review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIndividual participant data that underlie results after deidentification could be provided to researchers to achieve aims in a methodologically sound proposal approved by an independent review committee up to 36 months after article publication.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTPB\u0026rsquo;s PhD studies are sponsored by a University of Calgary\u0026nbsp;Mitacs\u0026nbsp;grant co-sponsored by\u0026nbsp;Quanovate\u0026nbsp;Tech, developers of the Mira urine hormone fertility monitor. The remaining authors report no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was provided for this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to thank the participants who contributed data for this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCromack SC, Walter JR. Consumer wearables and personal devices for tracking the fertile window. Am J Obstet Gynecol. 2024;\u003c/li\u003e\n\u003cli\u003eQueenan JT, Jennings VH, Hertzen H von, Spieler J. Introduction. Am J Obstet Gynecol. 1991;165(6):1977\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eMay K. Home tests to monitor fertility. American Journal of Obstetrics and Gynecology. 1991 Dec 1;165(6 Pt 2):2000\u0026ndash;2.\u003c/li\u003e\n\u003cli\u003eCollins WP. The evolution of reference methods to monitor ovulation. American Journal of Obstetrics and Gynecology. 1991 Dec 1;165(6 Pt 2):1994\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eLasley BL, Shideler SE, Munro CJ. A prototype for ovulation detection: pros and cons. American Journal of Obstetrics and Gynecology [Internet]. 1991 Dec 1;165(6 Pt 2):2003\u0026ndash;7. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed\u0026amp;Cmd=Retrieve\u0026amp;list_uids=1755459\u0026amp;dopt=abstractplus\u003c/li\u003e\n\u003cli\u003eBarnard G, Karsiliyan H, Kohen F. Idiometric assay, the third way: a noncompetitive immunoassay for small molecules. American Journal of Obstetrics and Gynecology [Internet]. 1991 Dec 1;165(6 Pt 2):1997\u0026ndash;2000. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed\u0026amp;Cmd=Retrieve\u0026amp;list_uids=1755457\u0026amp;dopt=abstractplus\u003c/li\u003e\n\u003cli\u003eBrown JB, Holmes J, Barker G. Use of the Home Ovarian Monitor in pregnancy avoidance. American Journal of Obstetrics and Gynecology. 1991 Dec;165(6 Pt 2):2008\u0026ndash;11.\u003c/li\u003e\n\u003cli\u003eQueenan JT, O\u0026rsquo;brien GD, Bains LM, Simpson J, Collins WP, Campbell S. Ultrasound Scanning of Ovaries to Detect Ovulation in Women**Supported by the Special Programme of Research, Development and Training in Human Reproduction, World Health Organization.\u0026dagger;\u0026dagger;Presented at the Thirty-Sixth Annual Meeting of The American Fertility Society, March 18 to 22, 1980, Houston, Tex. Fertil Steril. 1980;34(2):99\u0026ndash;105.\u003c/li\u003e\n\u003cli\u003eFlynn AM, Docker M, Brown JB, Kennedy KI. Ultrasonographic patterns of ovarian activity during breastfeeding. American Journal of Obstetrics and Gynecology. 1991 Dec;165(6 Pt 2):2027\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eDiaz A, Laufer MR, Breech LL. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstetrics Gynecol. 2015;126(6):e143\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eHoughton LC. Menstruation as the Next Vital Sign. JAMA Netw Open. 2024;7(5):e2412778.\u003c/li\u003e\n\u003cli\u003eMu Q, Hanson L, Hoelzle J, Fehring RJ. Young Women\u0026rsquo;s Knowledge About Fertility and Their Fertility Health Risk Factors. Journal of obstetric, gynecologic, and neonatal nursing : JOGNN / NAACOG. 2019 Jan 23;48(2):153\u0026ndash;62.\u003c/li\u003e\n\u003cli\u003eMansfield PK, Voda A, Allison G. Validating a pencil-and-paper measure of perimenopausal menstrual blood loss. Women\u0026rsquo;s Heal Issues. 2004;14(6):242\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eEcochard R, Leiva R, Bouchard T, Boehringer H, Direito A, Mariani A, et al. Use of urinary pregnanediol 3-glucuronide to confirm ovulation. Steroids. 2013 Jul;78(10):1035\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003eBouchard TP, Fehring RJ, Schneider M. Pilot Evaluation of a New Urine Progesterone Test to Confirm Ovulation in Women Using a Fertility Monitor. Frontiers in public health. 2019 Jul 2;7:305.\u003c/li\u003e\n\u003cli\u003eLi H, Gibson EA, Jukic AMZ, Baird DD, Wilcox AJ, Curry CL, et al. Menstrual cycle length variation by demographic characteristics from the Apple Women\u0026rsquo;s Health Study. npj Digit Med. 2023;6(1):100.\u003c/li\u003e\n\u003cli\u003eFehring R, Schneider M, Raviele K. Variability in the Phases of the Menstrual Cycle. Journal of Obstetric [Internet]. 2006; Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed\u0026amp;cmd=Retrieve\u0026amp;dopt=AbstractPlus\u0026amp;list_uids=15766872558426156120\u003c/li\u003e\n\u003cli\u003eFehring RJ, Schneider M. Variability in the hormonally estimated fertile phase of the menstrual cycle. Fertility and Sterility. 2008;90(4):1232\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eBrown JB. Types of ovarian activity in women and their significance: the Continuum (a reinterpretation of early findings). Human reproduction update. 2011;17(2):141\u0026ndash;58.\u003c/li\u003e\n\u003cli\u003eBouchard TP, Fehring RJ, Mu Q. Quantitative Versus Qualitative Estrogen and Luteinizing Hormone Testing for Personal Fertility Monitoring. Expert Rev Mol Diagn. 2021;21(12):1349\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003eHart RJ, D\u0026rsquo;Hooghe T, Dancet EAF, Aurell R, Lunenfeld B, Orvieto R, et al. Self-Monitoring of Urinary Hormones in Combination with Telemedicine \u0026mdash; a Timely Review and Opinion Piece in Medically Assisted Reproduction. Reprod Sci. 2022;29(11):3147\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003eNakhuda GS, Li N, Yang Z, Kang S. At-home urine estrone-3-glucuronide quantification predicts oocyte retrieval outcomes comparably with serum estradiol. F S Reports. 2023;4(1):43\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eDireito A, Bailly S, Mariani A, Ecochard R. Relationships between the luteinizing hormone surge and other characteristics of the menstrual cycle in normally ovulating women. Fertility and Sterility. 2013 Jan;99(1):279\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003eEcochard R, Bouchard T, Leiva R, Abdulla S, Dupuis O, Duterque O, et al. Characterization of hormonal profiles during the luteal phase in regularly menstruating women. Fertility and Sterility. 2017 Jul;108(1):175-182.e1.\u003c/li\u003e\n\u003cli\u003eRoos J, Johnson S, Weddell S, Godehardt E, Schiffner J, Freundl G, et al. Monitoring the menstrual cycle: Comparison of urinary and serum reproductive hormones referenced to true ovulation. The European journal of contraception \u0026amp; reproductive health care : the official journal of the European Society of Contraception. 2015 May 27;20(6):1\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eHills E, Woodland MB, Divaraniya A. Using Hormone Data and Age to Pinpoint Cycle Day within the Menstrual Cycle. Medicina. 2023;59(7):1348.\u003c/li\u003e\n\u003cli\u003ePattnaik S, Das D, Venkatesan VA, Rai A. Predicting serum hormone concentration by estimation of urinary hormones through a home-use device. Hum Reproduction Open. 2022;2023(1):hoac058.\u003c/li\u003e\n\u003cli\u003eWegrzynowicz AK, Beckley A, Eyvazzadeh A, Levy G, Park J, Klein J. Complete Cycle Mapping Using a Quantitative At-Home Hormone Monitoring System in Prediction of Fertile Days, Confirmation of Ovulation, and Screening for Ovulation Issues Preventing Conception. Medicina. 2022;58(12):1853.\u003c/li\u003e\n\u003cli\u003eWang R, Mol BWJ. The Rotterdam criteria for polycystic ovary syndrome: evidence-based criteria? Hum Reprod. 2016;32(2):261\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eChauvin S, Cohen-Tannoudji J, Guigon CJ. Estradiol Signaling at the Heart of Folliculogenesis: Its Potential Deregulation in Human Ovarian Pathologies. Int J Mol Sci. 2022;23(1):512.\u003c/li\u003e\n\u003cli\u003eArroyo A, Laughlin GA, Morales AJ, Yen SSC. Inappropriate Gonadotropin Secretion in Polycystic Ovary Syndrome: Influence of Adiposity1. J Clin Endocrinol Metab. 1997;82(11):3728\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003eBouchard T, Blackwell L, Brown S, Fehring R, Parenteau-Carreau S. Dissociation between Cervical Mucus and Urinary Hormones during the Postpartum Return of Fertility in Breastfeeding Women: The Linacre Quarterly. 2018 Nov 30;85(4):399\u0026ndash;411.\u003c/li\u003e\n\u003cli\u003eSchneider MM, Fehring RJ, Bouchard TP. Effectiveness of a Postpartum Breastfeeding Protocol for Avoiding Pregnancy. Linacre Q. 2023 Jul 27;002436392311672.\u003c/li\u003e\n\u003cli\u003eFehring R, Barron M, Schneider M. Protocol for determining fertility while breastfeeding and not in cycles. Fertility and Sterility [Internet]. 2005;84(3):805\u0026ndash;7. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed\u0026amp;cmd=Retrieve\u0026amp;dopt=AbstractPlus\u0026amp;list_uids=16366404905934012477\u003c/li\u003e\n\u003cli\u003eBouchard TP, Doyle-Baker PK, Yong PJ, Fehring RJ, Schneider M. Validating At-Home Urinary Hormone Measurements in Postpartum and Perimenopause Fertility Transitions. Women\u0026rsquo;s Health Reports. 2024;(in press).\u003c/li\u003e\n\u003cli\u003eBouchard TP, Schweinsberg K, Smith A, Schneider M. Using Quantitative Hormone Monitoring to Identify the Postpartum Return of Fertility. Medicina. 2023;59(11):2008.\u003c/li\u003e\n\u003cli\u003eKhoudary SRE, Greendale G, Crawford SL, Avis NE, Brooks MM, Thurston RC, et al. The menopause transition and women\u0026rsquo;s health at midlife: a progress report from the Study of Women\u0026rsquo;s Health Across the Nation (SWAN). Menopause (N York, Ny). 2019;26(10):1213\u0026ndash;27.\u003c/li\u003e\n\u003cli\u003eHarlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, et al. Executive summary of the Stages of Reproductive Aging Workshop \u0026amp;plus; 10. Menopause. 2012;19(4):387\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eMeyers M, Fehring RJ, Schneider M. Case Reports from Women Using a Quantitative Hormone Monitor to Track the Perimenopause Transition. Medicina. 2023;59(10):1743.\u003c/li\u003e\n\u003cli\u003eMunro MG, Critchley HOD, Fraser IS. The FIGO systems for nomenclature and classification of causes of abnormal uterine bleeding in the reproductive years: who needs them? American Journal of Obstetrics and Gynecology. 2012 Oct;207(4):259\u0026ndash;65.\u003c/li\u003e\n\u003cli\u003eBouchard T, Yong P, Doyle-Baker P. Establishing a Gold Standard for Quantitative Menstrual Cycle Monitoring. Medicina. 2023 Aug 24;59(9):1513.\u003c/li\u003e\n\u003cli\u003eDunson DB, Baird DD, Wilcox AJ, Weinberg CR. Day-specific probabilities of clinical pregnancy based on two studies with imperfect measures of ovulation. Hum Reprod. 1999;14(7):1835\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eStujenske TM, Mu Q, Capotosto MP, Bouchard TP. Survey Analysis of Quantitative and Qualitative Menstrual Cycle Tracking Technologies. Medicina. 2023 Aug 22;59(9):1509.\u003c/li\u003e\n\u003cli\u003eTurner RJ, Kerber IJ. A theory of eu-estrogenemia. Menopause. 2017;24(9):1086\u0026ndash;97.\u003c/li\u003e\n\u003cli\u003eHale GE, Hughes CL, Burger HG, Robertson DM, Fraser IS. Atypical estradiol secretion and ovulation patterns caused by luteal out-of-phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopausal transition. Menopause. 2009;16(1):50\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Connor KA, Ferrell R, Brindle E, Trumble B, Shofer J, Holman DJ, et al. Progesterone and ovulation across stages of the transition to menopause. Menopause. 2009;16(6):1178\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eEcochard R, Guillerm A, Leiva R, Bouchard T, Direito A, Boehringer H. Characterization of follicle stimulating hormone profiles in normal ovulating women. Fertil Steril. 2014;102(1):237-243.e5.\u003c/li\u003e\n\u003cli\u003eAbdullah S, Bouchard T, Leiva R, Boehringer H, Iwaz J, Ecochard R. Distinct urinary progesterone metabolite profiles during the luteal phase. Hormone Mol Biology Clin Investigation. 2022;0(0).\u003c/li\u003e\n\u003cli\u003eJohnson S, Weddell S, Godbert S, Freundl G, Roos J, Gnoth C. Development of the first urinary reproductive hormone ranges referenced to independently determined ovulation day. Clinical chemistry and laboratory medicine : CCLM / FESCC. 2015 Jan 17;0(0):1099\u0026ndash;108.\u003c/li\u003e\n\u003cli\u003eZwingerman R, Chaikof M, Jones C. A Critical Appraisal of Fertility and Menstrual Tracking Apps for the iPhone. J Obstetrics Gynaecol Can. 2020;42(5):583\u0026ndash;90.\u003c/li\u003e\n\u003cli\u003eYong PJ, Khan Z, Wahl K, Bouchard TP, Doyle-Baker PK, Prior JC. Menstrual Health Literacy, Equity and Research Priorities. J Obstetrics Gynaecol Can. 2024;(in press).\u003c/li\u003e\n\u003cli\u003eClearblue Menopause Stage Indicator [Internet]. [cited 2024 Dec 12]. Available from: https://www.clearblue.com/healthcare-professionals/menopause/stage-indicator\u003c/li\u003e\n\u003cli\u003eDjerassi C. Fertility awareness: jet-age rhythm method? Science. 1990;248:1061\u0026ndash;2.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 3","content":"\u003cp\u003eTable 3 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Menstrual Cycle, Ovulation, Estrone-3-glucuronide (E13G), luteinizing hormone (LH), Pregnanediol glucuronide (PDG)","lastPublishedDoi":"10.21203/rs.3.rs-6669318/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6669318/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eReproductive hormones of the fertile window are often referenced to women in regular cycles, but this may not be representative of the hormonal profiles of women in different circumstances like polycystic ovarian syndrome, the postpartum period, and the perimenopause transition. This observational cohort study sought to identify the variability in the hormones of the fertile window in various reproductive categories and to establish potential thresholds for each category based on hormone measurements with the Mira urinary hormone monitor.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 57 women (ages 22\u0026ndash;51) in various circumstances (regular cycles, polycystic ovarian syndrome, postpartum and perimenopause) tracked Mira urine hormone measurements (estrone-3-glucuronide, luteinizing hormone, pregnanediol glucuronide), contributing 444 cycles of data. Using additive mixed models, hormone values were stratified by the four different reproductive categories. The perimenopause and polycystic ovararian syndrome groups demonstrated relative hypoestrogenic states, while the perimenopause group showed low luteal pregnanediol glucuronide and the polycystic ovarian syndrome group showed high luteal pregnanediol glucuronide. The perimenopause group had higher luteinizing hormone values throughout the whole cycle.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe fertile window hormone thresholds vary depending on a woman\u0026rsquo;s specific reproductive category. Women in different circumstances should not necessarily use the same hormonal thresholds for the fertile window and ovulation. A larger dataset with ultrasound correlation to ovulation is required to delineate the fertile window with more precision. Hormone differences across the menstrual cycle could be used for targeted treatments in polycystic ovarian syndrome and perimenopause women.\u003c/p\u003e","manuscriptTitle":"Modeling Fertile Window Differences Across the Reproductive Lifespan with Quantitative Urine Hormone Monitoring of the Menstrual Cycle","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-03 14:10:40","doi":"10.21203/rs.3.rs-6669318/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-04T22:55:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-03T07:58:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-22T04:31:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"98067519293759447064596182343905150456","date":"2025-06-08T20:46:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"131225243890084613660326339142825690809","date":"2025-06-01T23:31:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-01T22:59:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-22T01:32:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-21T14:56:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Ovarian Research","date":"2025-05-15T06:15:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"50cec49b-c4da-4356-9587-f7bd28471e3b","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T00:08:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-03 14:10:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6669318","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6669318","identity":"rs-6669318","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}