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Comparative Assessment of Serum versus Menstrual Blood for Diagnostic Purposes: A Pilot Study

Authors:
Sci Forschen
Open HUB for Sc i e n t if i c R e s e a r c h
Journal of Clinical and Laboratory Medicine
ISSN 2572-9578 | Open Access
J Clin Lab Med | JCLM
1
RESEARCH ARTICLE
Comparave Assessment of Serum versus Menstrual Blood for Diagnosc
Purposes: A Pilot Study
Sara Naseri, Klaira Lerma, and Paul D Blumenthal*
Department of Obstetrics and Gynecology, School of Medicine, Stanford University, CA, USA
Received: 03 Oct, 2019 | Accepted: 13 Nov, 2019 | Published: 20 Nov, 2019
Volume 4 - Issue 2
*Corresponding author: Paul Blumenthal, Pasteur Drive, Stanford, USA, Tel: 650-721-1562; E-mail: pblumen@stanford.edu
Citaon: Naseri S, Lerma K, Blumenthal PD (2019) Comparave Assessment of Serum versus Menstrual Blood for Diagnosc Purposes: A
Pilot Study. J Clin Lab Med 4(2): dx.doi.org/10.16966/2572-9578.130
Copyright: © 2019 Naseri S, et al. This is an open-access arcle distributed under the terms of the Creave Commons Aribuon License,
which permits unrestricted use, distribuon, and reproducon in any medium, provided the original author and source are credited.
Abstract
Background: Blood testing remains an essential component of diagnosis and prevention of disease. Phlebotomists, Laboratory Infrastructure,
Storage, Collection, and Transport are required for Current Methods of Blood Collection. Menstrual Blood has many similar characteristics
to circulating blood but has not previously been assessed as a Potential Diagnostic Resource.
Objective: To assess if biomarkers derived from menstrual blood correlate with systemic blood.
Study design: This was a prospective, observational pilot study of healthy reproductive-aged women. We chose a panel of 9 Biomarkers,
used in preventative health assessments and for following clinical conditions, and compared systemic and menstrual blood levels.
Results: Eighty-Four volunteers were screened over two months; 35 provided a menstrual and serum sample, of which 20 had a sample
adequate for analysis. Overall, the correlation was observed, particularly for 7 Biomarkers, with no statistically significant differences
between the mean menstrual and serum values. These include cholesterol (P for differences in means=0.89, R2 for correlation=0.89),
Creatinine (P=0.32, R2=0.94), HSCRP (P=0.89, R2=0.99), LDL (P=0.21, R2=0.84), Triglycerides (P=0.45, R2=0.89), Hba1c (P=0.54, R2=0.80),
and HDL (P=0.33, R2=0.77). One biomarker, FSH (P<0.001, R2=0.97), was less directly comparable to systemic blood, but a linear relationship
was recognized suggesting that the correlation could be mathematically derived, and therefore diagnostic utility is possible.
Conclusion: Based on our results, menstrual blood can reliably estimate levels of several biomarkers and may be a promising option for non-
invasive collection of blood for diagnosis and health monitoring. Larger trials are needed to confirm these findings.
of disorders were present in menstrual uid [1]. ese disorders
include endometriosis, breast, Cervical, Ovarian and Endometrial
Cancer. Several other studies have detected the presence of Human
Papilloma Virus (HPV) in menstrual blood implying that it may be
useful for non-invasive screening for cervical cancer or pre-cancer
[2,3]. Furthermore, menstrual blood has been studied for screening
or diagnosis of Sexually Transmitted Infections (STIS). Alary M, et
al. explored the potential of using vaginal uid collected in menstrual
pads for Chlamydia detection. is proved to have sensitivity and
specicity equivalent to, or even higher than, existing methods,
including vaginal swabs or urine samples [4]. ese data combine
to provide support for the potential utility of menstrual blood-based
testing as a non-invasive alternative blood source for diagnostic or
therapeutic analysis.
Despite this apparent potential, menstrual blood remains a
relatively uninvestigated area for diagnostics; no published literature
explores the correlation of systemic versus menstrual-based blood
for assessing biomarkers relative to indicators of health or disease.
Introduction
Whole blood or Serum (Systemic Blood) is commonly used to
diagnose or monitor many medical conditions. However, obtaining
a specimen is an invasive procedure, requiring medical assistance.
It can be inconvenient, costly, painful, and anxiety-provoking. Most
reproductive-aged women menstruate regularly, and while menstrual
blood shares many characteristics with systemic blood, it has not
been subject to rigorous clinical investigations for diagnostic and
therapeutic purposes.
Menstrual blood is composed of three distinct body uids: whole
blood, vaginal uid, and the cells and uid of the late Secretory Phase
of the endometrial lining and the cervix, shed during menstruation.
Molecular proteomic studies have shown considerable correlation
with systemic blood; however, menstrual blood also contains
additional uids [1]. Specically, at least 385 additional proteins
can be detected in menstrual blood when compared with systemic
blood [1]. In 2012 Siegel D, et al. rst dened the proteomics of
menstrual blood, and found that several biomarkers for a wide range
Sci Forschen
Open HUB for Sc ie n t i f i c R e s e a r c h
Citaon: Naseri S, Lerma K, Blumenthal PD (2019) Comparave Assessment of Serum versus Menstrual Blood for Diagnosc Purposes:
A Pilot Study. J Clin Lab Med 4(2): dx.doi.org/10.16966/2572-9578.130 2
Journal of Clinical and Laboratory Medicine
Open Access Journal
To assess this, we conducted a proof-of-concept study, comparing
menstrual blood to systemic blood. We hypothesized that if menstrual
blood biomarkers correlated with systemic blood, this alternative
testing method could have potential as a convenient, non-invasive
and cost-eective approach to blood analysis for both diagnosis
and therapeutics. If found reliable, such an approach could enhance
opportunities for early disease detection and regular health monitoring
among women who menstruate.
Materials and Methods
is was a prospective, observational, pilot study of healthy
reproductive-aged women. Interested women completed a telephone
screening to assess eligibility and willingness to participate. Exclusion
criteria included being younger than 18 years of age, older than 45
years, postmenopausal, not menstruating regularly, and uncomfortable
with or clinically unable to use a menstrual cup for menstrual blood
collection.
ose who were eligible per telephone screening were invited to
an in-person meeting. During the meeting the study processes were
explained in detail and instructions of how to use a menstrual cup were
given to ensure participants were aware and comfortable using it for the
menstrual blood collection. Demographic and other information such
as age, weight, birth control usage, expected dates for menstruation,
and health issues and concerns, were collected. All participants signed
consent forms and were given a study kit containing a menstrual cup
and two blood collection tubes. e menstrual cup (diva international
inc., on, Canada) used for menstrual blood collection is a exible
menstrual cup that is worn internally, around the cervix to collect,
rather than absorb, menstrual ow. It is hypo-allergenic, latex-free
and safe when used as directed. e materials used in the study are
commonly used and are FDA, CE or who-prequalied. e study was
approved by the Stanford Institutional Review Board (IRB-35817).
Participants were instructed to contact study sta on the rst day of
their period, being the rst day with actual ow. at day, participants
were instructed to stop intake of food aer midnight. On the second
day of their period participants were instructed to use the menstrual
cup for three hours, starting at the time they woke up in the morning,
and then immediately pour the collected menstrual blood into the
designated blood collection tubes. e second day was chosen due
to convenience and because the second day of menstruation for
most participants was found to be the day with the heaviest ow of
menstrual blood. When participants presented at the study site-a
venous blood draw was performed, and the menstrual blood samples
were collected. e venous samples were collected on the same day as
the menstrual blood samples. Neither the participants nor study sta
observed any clotting in the menstrual blood samples. Both blood
samples were pipetted onto Dried Blood-Spot (DBS) blood collection
cards (advance DX inc., AZ, USA). DBS is considered interchangeable
with venepuncture [5,6] and was used as a convenient and cost-
eective way to transport blood samples to the laboratory for analysis.
Because both samples were collected on DBS and both samples were
analyzed with same methods and by the same laboratory, any eect
on the samples using DBS would be applicable to both samples and
therefore the comparison of the two samples is valid. A total of four
cards per sample type were utilized. e eight blood collection cards
per participant were shipped on the same day to a CLIA/CAP Certied
Laboratory and DBS specialist, us specialty (San Diego, CA, USA),
where the coded samples were analyzed. All samples were provided to
the lab with no indication as to the source (i.e., menstrual or serum), so
that analyses were performed in a “blinded” fashion. All participants
were compensated for their travel and time spent in clinic.
Results were analyzed using paired t-tests to compare mean
values of systemic blood to menstrual blood; condence intervals
were calculated to provide insight into the magnitude of the mean
dierences. Further, via correlation analysis of the paired samples,
we analyzed whether it is possible to predict systemic blood results
based on menstrual blood results. We used the method of least squares
to create the trend line. Such a calculation would mean that systemic
blood values are not necessarily identical to menstrual blood results,
but that correlations could be mathematically predicted, indicating that
certain systemic blood biomarkers can be estimated from menstrual
blood. To assess the strength of the linear relationship we used Pearson
correlation coecient, which varies from -1 (perfect linear negative
relationship) to +1 (perfect linear positive relationship) with values
around 0 corresponding to weak relationship.
Results
Between March 2016 and March 2017, 145 volunteers were evaluated
for participation, and pre-procedure meetings were arranged for 84
eligible women, who represented a convenience sample. We enrolled
and collected menstrual and systemic blood from 35 participants.
For 15 participants, the volume of menstrual blood collected was
insucient for analysis and those participants were excluded, leaving
20 participants in this analysis. Our participants were young and
healthy, and the majority reported regular menstrual periods [n=20,
96.2%] (Table 1).
In comparing paired samples of systemic blood to menstrual
blood (n=20), there were no statistically signicant dierences among
values for cholesterol, FSH, HBA1C, and HSCRP. For other markers,
specically Creatinine, glucose, LDL, and triglycerides, the mean
dierence between the pairs was statistically signicantly dierent;
in these analyses several outliers were observed from the trend. In all
cases of statistically signicant dierences between the paired samples,
serum values were higher than menstrual values. Systemic blood
demonstrated much higher levels of glucose compared to menstrual
blood (Table 2).
Systemic blood values were signicantly correlated with their
menstrual blood counterparts (p<0.05), except for glucose (correlation
coecient below 0.2, p>0.05). Regression analysis revealed coecients
that demonstrated a strong linear relationship for multiple analytes
(p<0.05), table 3, including cholesterol (r=0.942, p<0.001), Creatinine
(r=0.973, p<0.001), FSH (r=0.982, p<0.001), HSCRP r=0.996,
p<0.001), and triglycerides (r=0.944, p<0.001). However, there was
Age, mean (± SD) 28 ± 8.7
Race, n (%)
White 14 (70.0)
Asian 4 (20.0)
Other 2 (10.0)
Body Mass Index (BMI), mean (± SD) 21.9 ± 3.3
Regular menstrual cycle, n (%) 25 (96.2)
Hygiene product used regularly, n (%)
Tampons only 6 (30.0)
Pads only 3 (15.0)
Menstrual cup 3 (15.0)
Both tampons and pads 8 (40.0)
Table 1: Parcipant Characteriscs, N=20.
Sci Forschen
Open HUB for Sc ie n t i f i c R e s e a r c h
Citaon: Naseri S, Lerma K, Blumenthal PD (2019) Comparave Assessment of Serum versus Menstrual Blood for Diagnosc Purposes:
A Pilot Study. J Clin Lab Med 4(2): dx.doi.org/10.16966/2572-9578.130 3
Journal of Clinical and Laboratory Medicine
Open Access Journal
poor correlation between menstrual and systemic blood for glucose
(r=0.195, p=0.411). e correlation analysis showed that although
the FSH was one of the biomarkers for which we observed signicant
dierences in systemic and menstrual blood values, using the derived
equation, it was possible to predict systemic blood FSH (r=0.982)
knowing the result based on menstrual blood. e relationships
between systemic and menstrual blood samples for some of the
biomarkers are illustrated in gure 1.
Conclusion
Our analysis indicates statistically signicant correlation of values
for eight biomarkers in systemic and menstrual blood samples:
cholesterol, Creatinine, HSCRP, LDL, triglycerides, hba1c HDL, and
FSH (Table 1). ese results indicate that biomarkers in menstrual blood
can approximate systemic blood levels and, based on the observations
reported here, menstrual blood could be used to estimate the serum
levels of these 8 biomarkers. When there was a statistically signicant
mean dierence between systemic and menstrual blood (e.g., FSH), it
was possible to generate a formula correlating the systemic blood to
the menstrual blood which resulted in a high correlation coecient.
Of all the analytes tested, there was a much more marked dierence
between serum and menstrual blood for glucose. We hypothesize this
is because the resident ora in the vagina used the glucose for their
own metabolic needs, thus lowering the value relative to serum, where
there are no similar resident bacteria.
While these data are promising, the data presented here is limited
by a small sample size, and the stability and method of collection of
menstrual blood was not optimized, leading to several failed samples.
In addition, when the dierence in paired means was statistically
signicant, the menstrual values were always lower than the serum
values, indicating possible degradation of the analytes in the menstr ual
cup. Also, for those analytes showing statistically signicant dierences
between the means, the dierence appeared to be due to some pairs
showing huge dierences compared to the majority of pairs showing
minor or no dierences. Larger studies will likely provide better results
and reference ranges for these and, possibly, other biomarkers, with
outliers having less eect on the overall analysis.
Another limitation was the use of menstrual cups since 1) some
women declined participation in the study because they were
uncomfortable with this method of collection, and 2) it is possible that
blood sitting in the menstrual cup could become degraded if le too
long before analysis. A dierent device, such as a modied menstrual
pad, could be a more convenient and comfortable method of collection
and could potentially improve both participation rates and the quality
of the specimen for analysis. Future studies using both larger sample
sizes and utilizing an optimized system for collecting menstrual blood
are needed to better establish these reference ranges as well as any
adjustment formulas for relevant biomarkers. Such formulas will allow
approximation of systemic blood results based on menstrual blood
results with an improved degree of accuracy.
Further study is needed to establish many of the reference ranges
and correlation information. We plan to expand the number of women
tested to establish reference ranges and adjustment formulas for each
biomarker and optimize the collection of menstrual blood, using a
specially designed menstrual pad that will yield a dried blood spot for
analysis instead of pooled menstrual blood in a cup.
Despite our limitations, from a preliminary, “proof of concept”,
perspective, these results provide data to support the potential of
using menstrual blood-based testing as an alternative to systemic
blood analysis. Such an alternative testing approach has the potential
to change practice and potentially improve safety, convenience, and
cost eectiveness of blood analysis for both diagnosis and therapeutic
monitoring among menstruating women. e approach could also
enhance opportunities for early detection and regular health monitoring
worldwide especially in rural areas and developing countries where
the population has limited access to medical professionals.
Acknowledgments
We would like to thank Professor Maecker Holden, PhD,
Stanford University, Cancer Biology, and Yael Rosenberg-Hasson,
Biomarker Systemic Blood Menstrual Blood Mean 95% Condence Interval Of The Dierence
Dierence
Cholesterol(mg/Dl) 164.86 ± 36.84 163.20 ± 38.53 1.66 -4.38 to 7.70
Creanine (mg/Dl) 1.04 ± 0.75 1.28 ± 0.72 -0.24 -0.32 to -0.16
FSH (Uiu/Ml) 4.99 ± 2.33 4.86 ± 2.49 0.13 -0.09 to 0.35
Glucose (mg/Dl) 90.58 ± 8.63 9.91 ± 10.30 80.67 75.01 to 86.33
Hba1c (%) 5.35 ± 0.36 5.27 ± 0.45 0.08 -0.02 to 0.18
HDL (mg/Dl) 63.10 ± 13.27 59.22 ± 11.29 3.88 0.92 to 6.83
Hscrp (mg/Dl) 4.12 ± 6.02 3.86 ± 6.00 0.26 -0.01 to 0.51
LDL (mg/Dl) 95.79 ± 30.67 83.67 ± 28.91 12.12 6.45 to 17.78
Triglycerides(mg/Dl) 84.40 ± 51.55 71.91 ± 51.12 12.49 4.41 to 20.57
Table 2: Paired Sample Comparison of Systemic and Menstrual Blood Samples, N=20.
FSH: Follicle Smulang Hormone; HbA1c: Hemoglobin A1c; HDL: High-Density Lipoprotein; HSCRP: High Sensivity C Reacve Protein; LDL: Low
Density Lipoprotein.
Pearson’s Correlaon 95% CI P-Value
Cholesterol 0.942 0.86-0.98 <0.001
Creanine 0.972 0.93-0.99 <0.001
FSH 0.982 0.95-0.99 <0.001
Glucose 0.195 0.27-0.59 0.41
Hba1c 0.892 0.74-0.96 <0.001
HDL 0.88 0.71-0.95 <0.001
Hscrp 0.996 0.99-1.00 <0.001
LDL 0.919 0.80-0.97 <0.001
Triglycerides 0.944 0.86-0.98 <0.001
CI: Condence Interval; FSH: Follicle Smulang Hormone; HbA1c: He-
moglobin A1c; HDL: High Density Lipoprotein; HSCRP: High Sensivity C
Reacve Protein; LDL: Low Density Lipoprotein.
Table 3: Pearson Correlaon Coecients between Menstrual and Sys-
temic Blood Samples.
Sci Forschen
Open HUB for Sc ie n t i f i c R e s e a r c h
Citaon: Naseri S, Lerma K, Blumenthal PD (2019) Comparave Assessment of Serum versus Menstrual Blood for Diagnosc Purposes:
A Pilot Study. J Clin Lab Med 4(2): dx.doi.org/10.16966/2572-9578.130 4
Journal of Clinical and Laboratory Medicine
Open Access Journal
Figure 1: Correlaon between menstrual and serum blood for selected analytes.
Technical Director, Institute for Immunity, Transplantation, and
Infection, for their support in the initial validation phase. We also
acknowledge Joel Zinda at US Specialty Labs for help with sample
analysis, and Megan Fitzpatrick, MD, for careful reading of the
manuscript.
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... It is a complex biological fluid made up of three different types of body fluids: whole blood, vaginal fluid, and uterine wall cells and their secretions [60]. While proteomic studies have revealed that menstrual blood and systemic blood share some protein indicators in common, there is evidence of few biomarkers exclusive to menstrual blood [61]. Multiple proteomic methodologies and analytical methods were used in a study by Yang et al., which resulted in the discovery of 385 proteins, unique to menstrual blood [60]. ...
... Multiple proteomic methodologies and analytical methods were used in a study by Yang et al., which resulted in the discovery of 385 proteins, unique to menstrual blood [60]. This work defined the proteomic composition of menstrual blood for the first time [60,61]. Additionally, this study concluded by emphasizing that menstrual fluid contains protein biomarkers valuable for a variety of illnesses, including cervical, breast, ovarian, and uterine cancers [60]. ...
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