Abstract Presentation: Creighton Model Fertility Care System (CrMS) and pilot study of the midpoint, and points of change (POC) in the clinical window of sub-fertile cycles / Creighton Model Fertility Care System (CrMS), Maximum Last Spinbarkheit (LMS) and Transparency by "K" in the clinical window of sub-fertile cycles

José María Murcia Lora, MD, OB-GYN, PhD.

 

Introduction

The purpose of this work is to review the contribution that viscoelasticity and transparency can make, as a signal and biophysical marker of cervical secretion in the recognition of the fertility of the fertile window, based on the Creighton model (CrMs).

The objective of this brief introduction is to point out those concepts that are relevant to the changes observed in cervical secretion, and explain the production of estrogens by endocervical cells.

For this, it is convenient to review some basic concepts of the physiology of ovulation involved in the evolution of the pattern of cervical secretion in the fertile window, and fundamental for a process of growth, selection, recruitment, and follicular maturation to take place.

Each month the ovary has a follicular pool. To be rescued from this follicular reserve, preantral follicles need to have receptors for follicle-stimulating hormone (FSH), and be sensitive to the action of FSH. In such a way that the preantral follicle of 1 and 4 days can be subject to the rescue of the follicular pool, for a certain time and threshold (1).

In addition to having receptor stromal cells sensitive to the action of FSH, an adequate aromatization must be given in the antral follicle (2). This step is decisive in the process of providing a sufficient production of estrogens, to achieve adequate stimulation of the endocervical cells that produce L and S type secretions.

Around days 5-12 days of antral folic, the number of stromal cells increases significantly, the infliction of FSH decreases. And one of the events involved in this development is the effect known as the "snowball" "snowball-like effect". This effect plays an important multiplier and self-perpetuating role between receptors and stromal cells. The final stage of the dominant follicle is usually evidenced with a pre-ovulatory follicle of around 18 mm, which ends up being matured under the action of luteinizing hormone (LH). LH helps to complete an adequate maturation in the remodeling of the follicular cells of the granulosa, it continues with the aromatization of androgens from the theca cells, it intervenes in the final maturation of the oocyte,

In turn, these processes are enhanced by various signals; as is the redistribution of perifollicular flow, mediated by the vascular endothelial factor; growth factor (VEGF). This factor increases the blood supply around the follicle. The mediation of insulin-like growth factor (IGF) 1 has also been seen, as a mitogenic effect of estrogen-producing cells among others.

These mentioned changes are well correlated with the dynamics of follicular growth, and the elevation of the determinations in urine of estrone-3-glucuronide (E3G). The difference between the number of estrogens produced at the beginning of the cycle and at the ovulatory level is significant, which makes up the aforementioned physiological findings (4,5). The E3G determination increases from 20-30 ng / ml from day -6 relative to the estimated day of ovulation (EDO), until the day of ovulation, at which point the LH surge is normally detected greater than 30 IU / l (6). This peak generally occurs 24 to 48 hours before ovulation but is never after it.

In this way, the American Society for Reproductive Medicine (ASRM) has defined the physiological fertile window (BFW), as the first day in which estrone-3-glucuronide (E3G) is detected in urine, until the second day after the peak. of luteinizing hormone (LH), which usually ranges from <1 to> 7 days (7).

The fertile window recorded by the duration of the menstrual cycle is a procedure already studied by Wilcox (8). In Wilcox's study (8), he identifies in his series of regular cycles the possibility of finding the self-reported fertile window with a very wide margin between days 7 and 21 of the menstrual cycle (8). The possibility of being in the fertile window on the 4th day of the cycle in their study was 2%, by only interpreting the duration of the menstrual cycle, 17% on the 7th day of the cycle, and 54% between the 12th and 13th day of the cycle (8). However, in his study, the self-reported possibility of the menstrual cycle to be in the fertile window has a correlation index (CI) of 0.55, which makes it possible for the fertile woman to be between day 7 and 21 of the cycle by 50 % of cases in the fertile window.

Within the clinical classifications, Scarpa (9) describes the symptom of vaginal discharge mucus in 4 ranges. He manages to identify a mucus of greater fertile characteristics (a mucus 4) within the fertile window range between days 10 and 17 days. He finds in 50% of the cases, the presence of this type of mucus around day 13 of the cycle, and outside this interval less than 20%. Likewise, he associates a 30% probability of pregnancy, when he is within the range of greater probability of finding type mucus (4). Biegelow (10) describes the characteristics of cervical discharge on a fourth scale. He found a relationship between the quality of the cervical mucus and the probability of pregnancy, being the day -3 ODE higher for a type 4 mucus, which decreased as it moves away from ODE. Although the highest amount of type 4 mucus was evidenced in -2 ODE. These findings have also been corroborated using the Creighton Model Fertility Care System. Fehring (11) manages to frame by assessing the cervical mucus gradient (MMG) the detection of the peak of cervical mucus in 97% between the days (- 4 and + 4) around ovulation. These results are similar to those described by Hilgers (12) in 1978 where he shows peak day between (- 3 and + 3) in relation to the peak day of ovulation. In such a way, it has been possible through cervical secretion to identify and describe cervical secretion from the early follicular phase until the peak day of cervical mucus (13). The estimated day of ovulation (OED) has been recognized as one of the fundamental strategies to determine the signs that define or frame the fertile period. And the peak day of cervical secretion has been considered a point of reference that allows locating the evolutionary clinical changes of the fertile window (11, 12).

The restorative and restorative methodology of the menstrual cycle makes it possible to recover the natural biological approach related to the pathophysiological process of ovulation, in the field of fertility recognition (14).

Therefore, it is possible to apply concepts derived from ovulatory cycles in subfertile patients. It is estimated that around 12% to 15% of couples may experience infertility. The fertile window in subfertile patients has proven efficacy in spontaneous pregnancies (14). The changes observed in the biophysical parameters of the cervical secretion: as well as the volume, the viscoelasticity or spinnbarkheit, the transparency, and the crystallization of the cervical secretion, are likely to be used to identify the fertile window in subfertile patients (14). Currently, a greater success of pregnancies has been seen, in restorative fertile windows with duration and interval similar to a normal cycle (12).

For this reason, it can be said that from the clinical point of view, changes in the biophysical properties of cervical secretion have been integrated through various schools to evaluate the fertile window. The location of the fertile window by determining the cervical secretion has allowed the interpretation and recording of graphs of fertile or infertile characteristics of the cervical secretion. There are several classifications for the intake of cervical discharge observed in the vulva. All are observational methods that are based on the characteristics of the sensation, appearance, and consistency of the cervical discharge. Cervical discharge has an opaque appearance and is less translucent in the infertility phases, which becomes more transparent and elastic in the fertile phase.

Viscoelasticity has been recognized by many terms that describe the rheological properties of cervical mucus; viscosity, elasticity, viscoelasticity, plasticity, shrinkage, adherence, spinbarkheit, among others. The ability to lengthen or stretch the cervical discharge has been one of the classic parameters to assess the progression of cervical discharge throughout the cycle. The elasticity is greater on the days preceding the peak day, and during the peak day, as has been demonstrated by various clinical schools (12, 15-17). In this way, it is possible to assess the biophysical properties of cervical secretion, such as elasticity and transparency, as has been possible in several studies. The purpose of this work,

 

Menstrual Cycles

12 menstrual cycles of a 29-year-old female between 2017 and 2018 are included. The shortest cycle was 29 days and the longest 39 days in length. The first day of the cycle was considered as the first day of menstruation, and the last day of the cycle, the day before the start of the next menstruation. Twelve records of the typical evolution of cervical mucus were documented by recording the observation graphs of the vaginal discharge of cervical discharge (VDRS), with the Creighton Model Fertility Care System (CrMS). Twelve cycles were included in the study after having been the patient diagnosed with primary infertility, with a clinical history of more than one year of regular sexual intercourse without contraception. Organic and functional gynecological pathology was ruled out. A basic sterility study was carried out in which no detectable cause of female sterility was documented. The presence of treated oligoasthenozoospermia male factor was confirmed without significant improvement despite an effective sperm count (ESC) of 627,000 sperm. Sexual relations were maintained in the fertile window at the convenience of the patient. No pregnancy was achieved in any of the cycles.

Criteria to establish CFW: (mucus-mucus: CrMS / filancia ) and SFW: (Soft- CrMS / filancia )

The methodology used to evaluate the viscoelasticity factor was by measuring the approximate length in centimeters (cm) of the vaginal discharge of cervical discharge (VDRS). For this, the scale of the filancia graph established by observing the VDRS of filancia of Creighton Model Fertility Care System (CrMS) was used. The Spinbarkheit assessment of cervical discharge was exported to an Excel graph in cm, taking into account the following measurements: A: Sticky: 0.5 cm (Less than 0.65 cm, equivalent to ¼ inch). B: Tacky: 1 cm, equivalent to the lower value of the range of the CrMS classification between (1 - 2 cm); (1.27 - 1905 cm), which corresponds to (½ - ¾ of an inch for the CrMS system). C: Stretchy: 2.5 cm was recorded when the yarn was equal to or greater than 1 inch. The days on which there were dryness and no secretion were tabulated as 0. Table 1. summarizes the scale used to evaluate the parameter of viscoelasticity. Graph 1 describes the distribution of the mean values of viscoelasticity in cm throughout the menstrual cycle. Within the methodology used by the algorithm, the aforementioned scale was chosen, because this scale according to Cr MS describes better than other scales, the variation that occurs from the follicular phase of cervical secretion. In this way, it was possible to record the progressive evolutionary change in a systematic way from the left kurtosis of the fertile window to the postovulatory phase after the peak day as seen in Graph 1. the scale used to evaluate the viscoelasticity parameter is summarized. Graph 1 describes the distribution of the mean values of viscoelasticity in cm throughout the menstrual cycle. Within the methodology used by the algorithm, the aforementioned scale was chosen, because this scale according to Cr MS describes better than other scales, the variation that occurs from the follicular phase of cervical secretion. In this way, it was possible to record the progressive evolutionary change in a systematic way from the left kurtosis of the fertile window to the postovulatory phase after the peak day as seen in Graph 1. the scale used to evaluate the viscoelasticity parameter is summarized. Graph 1 describes the distribution of the mean values of viscoelasticity in cm throughout the menstrual cycle. Within the methodology used by the algorithm, the aforementioned scale was chosen, because this scale according to Cr MS describes better than other scales, the variation that occurs from the follicular phase of cervical secretion. In this way, it was possible to record the progressive evolutionary change in a systematic way from the left kurtosis of the fertile window to the postovulatory phase after the peak day as seen in Graph 1. The aforementioned scale was chosen because this scale according to Cr MS describes better than other scales, the variation that occurs from the follicular phase of cervical secretion. In this way, it was possible to record the progressive evolutionary change in a systematic way from the left kurtosis of the fertile window to the postovulatory phase after the peak day as seen in Graph 1. The aforementioned scale was chosen because this scale according to Cr MS describes better than other scales, the variation that occurs from the follicular phase of cervical secretion. In this way, it was possible to record the progressive evolutionary change in a systematic way from the left kurtosis of the fertile window to the postovulatory phase after the peak day as seen in Graph 1.

The clinical window in this article was established as CFW: (mucus-mucus: CrMS / filancia ) by means of the retrospective assessment of the mentioned scale taking into account the 6 days prior to the peak day: P (-6). The methodology used consisted in comparing the two fertile windows with ODE. To check the evolution in the characterization of the viscoelasticity parameter of the cervical secretion, the last day of maximum fertility was established, with the letter "P" for the peak day, according to the recognition rules for the Peak day of CrMS. The correlation test was performed to calculate the percentage of coincidence of the intervals, and the points of change (POC) between both windows.

The interval between both windows was evaluated CFW: (mucus-mucus: CrMS / filancia ) and SFW: (Soft- CrMS / filancia ) by means of a graph of means points, and correlation test of overlap of intervals. . The correlation test was performed to calculate the percentage of coincidence of the intervals, and the points of change (POC) between both windows.

The maximum transparency was registered with the letter "k" extracted from the CrMS registry, which was not taken into account to define, nor was the clinical fertile window CFW: (mucus-mucus CrMS / filancia ), nor EDO, nor was it considered in counts in the SFW calculation: ( Soft-CrMS / filancia ) . Thek "clear" is the maximum transparency standard on the CrMs scale. To assess the contributions of the variants of the peak day, Last Max Spinbarkheit (LMS) was considered, for which the estimation of the variations of Peak Day was taken into account in a descriptive way through the concept of: Last Max Spinbarkheit (LMS) & Transparency by "K" from CrMS. Different from the Peak Day concept, which is defined as any type of discharge that is clear, stretches or has isolated lubricative properties, or in combination with each other, according to Creighton Model Fertility Care System (CrMS).

 

Results:

The fertile window using CFW: CFW (mucus-mucus CrMS / filancia) it was possible to detect them in 100% of the cases. This study was based on isolating the determination of the filancia of cervical secretion, to assess its relationship with the peak day established by the Creighton Model Fertility Care System. Using the present series, it was possible to evaluate the elasticity of the VRDR by estimating the length in centimeters (cm). As the day of maximum fertility approached when ovulation was near, the cervical mucus stretched more, without breaking; The elasticity was observed to be greater during the days prior to the peak day and during the same peak day as observed in Graph 1. It was observed that the peak day in some cycles did not coincide with the day of maximum elasticity, which was observed in counts according to the standards of the CsMS model.CrMS / filancia ). The P (-6) interval was distributed between days 10 and 25 of the menstrual cycle as shown in Table 1. The clinical window of the SFW software : ( Soft-CrMS / filancia ) presented a normal distribution with a mean of 5.08 (SD + - 2.87). In graph 1, the records that make up each cycle with the two fertile windows are observed. The days in blue are those referring to the filancia described in the clinical scale of Table 1, it describes the days before the beginning of the fertile window, the fertile window and the filancia the days after the end of the fertile window of CFW: (mucus-mucus CrMS / filancia ) . The days detected by the algorithm are graphed in yellow as SFW: (Soft-CrMS / filancia ). It was possible to identify the days of the fertile window in yellow, both at the beginning and at the end of it, identified as points of change (POC). The concordance between the two fertile windows coincides in a percentage greater than 50% in 75% of the cycles, as shown in Table 2. In Graph 2, a graph of the middle points of each cycle of average filancia is made for both clinical fertile window, as for the fertile window of the algorithm. A midpoint concordance is displayed between each cycle of the two windows equivalent to the correlation coefficient of 0.71, as observed in Table 2.

Last Max Spinbarkheit (LMS) & Transparency by "K" according to CrMS, is described in Table 3. The k "clear" is the maximum clarity standard, in the Cretigton scale, its evidence is constant and improves the result of the algorithm, which has not been calculated in this study. Table 3 shows a systematic concordance between the K and the relationship with P. LMS is related to the maximum progression, filancia, and transparency. Apparently, the characteristics of the stretching and lubrication capacity are possible thanks to the physical properties of the endocervical crypts type L and S. In this series, all clinical windows registered this gradual rise in relation to LMS.

 

Conclusion:

The assessment of viscoelasticity in this series using Spinbarkheit allowed the fertile window to be detected in 100% of cases, and it was possible to describe the evolutionary pattern of cervical secretion throughout the menstrual cycle.

The scale of the CrMs model made it possible to extract the elasticity and transparency parameter as one more piece of information to help identify and characterize the peak day within the clinical window. Like the changes observed at the vulvar level in the elasticity of the cervical secretion, it could also be used to identify the beginning of the fertility window and the end of the fertile interval in sub-fertile patients in this series.

It was possible to establish a good correlation between the window calculated by the SFW software ( Soft-CrMS / filancia ), and the clinical window CFW: (mucus-mucus CrMS / filancia).

The prediction in the progression of the elasticity pattern of the cervical secretion allows detecting the typical evolution of the cervical secretion around 70% in this series.

In this context, it is evident that as the cervical mucus stretches more and increases elasticity, both the days before the peak day and the days after; the viscoelasticity parameter was correctly registered. The evolution and progression of the "K" in the elasticity of the cervical secretion was a parameter that together with the assessment of the maximum elasticity helped to identify and characterize the peak day of the fertile window.

Larger series are necessary to demonstrate the preliminary data presented. The quantitative contribution of the biophysical variables of the cervical secretion is a challenge for the applied development in the recognition of fertility, together with the rest of the physical variables of the cervical secretion in relation to the fluidity, elasticity, and sperm ascent.

 

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José María Murcia,  MD, OB-GYN, PhD.

Jose Maria Murcia, holds a Doctor of Medicine with a diploma in gynaecology and is a Member of the Spanish Society of Gynaecology and Obstetrics (S.E.G.O).
He began work as a physician for the Ministry of Health, Bogotá , Columbia followed by a in Gynaecology at the Clinic University of Pamplona, and was a research fellow at the Colombian Institute for Technology Studies and IEISA Foundation. He then moved to focus on research at the Navarra University where he completed his Ph.D. He has worked for over 22 years in Reproductive Medical Clinical Consulting and biomedical research with a focus on Biotechnology and Human Reproduction Biomarkers related to Natural Human Reproduction as an alternative to Artificial Reproduction Techniques in cases of Sub-fertility, Sterility or Infertility of both men and women, and has multiple publications. He has developed a BIOSENSOR FOR BIOPHYSICAL MEASUREMENT OF CERVICAL SECRETION, a non-invasive biosensor used to determine the optimum female fertility status as well as other projects.

José María Murcia,  MD, OB-GYN, PhD.

Antecedentes: José María Murcia nació el 9 de enero de 1965 en Bogotá, Colombia. Llegados a España, 1992. Educación: Doctor en Medicina, Universidad Javeriana, Bogotá, 1989. Diplomado en Obstetricia-Ginecología, Universidad de Navarra, Pamplona, España, 1995. Doctor por la Universidad de Navarra, Pamplona, España, 1996. Carrera: Médico general Ministerio de Salud, Bogotá 1990-1991. Residente en Ginecología en Clínica Universidad de Pamplona 1992-1995. Instituto Colombiano Educación Crédito y Estudios en Tecnología en Exterior Fellow 1992. Investigador Fundación IEISA 1994. Investigador Universidad de Navarra 1994-1996 Ph.D. Desde 1997, Consultor de Fertilidad y Ginecología Unidad (Logroño) La Rioja (España). Investigador independiente. Algunos trabajos con Biomarcadores en la Reproducción Humana Natural como alternativa a las Técnicas de Reproducción Artificial. Algunas publicaciones basadas en la antropología de la sexualidad como; Humanae Vitae, Ideología de género y futuro biotecnológico, Biomarcadores clínicos y Biotecnología en ventana fértil. Defensa de la vida humana: una mirada hacia el futuro. Diversos cursos realizados en biomarcadores clínicos, ecografía de fisiología ovárica y endocrinología ginecológica. Diversos cursos de formación Diagnóstico por ecografía transvaginal de patología benigna Ecografía obstétrico-ginecológica. Miembro de la Sociedad Española de Ginecología y Obstetricia (S.E.G.O). Dos novedades en Biotecnología y Reproducción Humana Solicitud de patente internacional (OMPI) 4 de octubre de 2018. Número de la siguiente invención: (WO2018178753) BIOSENSOR PARA MEDICIÓN BIOFÍSICA DE LA SECRECIÓN CERVICAL. Inventor. José María Murcia Lora. Nuevo biosensor no invasivo para determinar el estado de fertilidad femenino óptimo Referencia POD: TOES20190201001 Technology Transfer Enterprise Europe Network. Concurso de Patentes para Comercializar 2017 Colciencias. Con tecnología titulada: Biosensor para la medición de la secreción cervical. Número de registro 998-P. 11 de julio de 2017. Certificado de finalización. Fecha de finalización: 06/03/2017. Novedad Original Utility NC2018 / 0008438, solicitud concedida patente de invención fase prioritaria "DISPOSITIVO BIOSENSOR INTRACERVICAL AJUVANTE HÍBRIDO PARA LA CAPACITACIÓN ESPERMÁTICA". (PCT) Actual. Dr. José María Murcia Lora https://es.linkedin.com/in/biotecnolog%C3%Ada.