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Trial registered on ANZCTR


Registration number
ACTRN12619000049178
Ethics application status
Approved
Date submitted
14/12/2018
Date registered
15/01/2019
Date last updated
15/01/2019
Date data sharing statement initially provided
15/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Differential gene expression in peripheral blood mononuclear cells (PBMC) from healthy women during the normal menstrual cycle compared to women in menopause and healthy men.
Scientific title
Differential gene expression in PBMC from healthy women during the normal menstrual cycle compared to women in menopause and healthy men.
Secondary ID [1] 296810 0
Nil known
Universal Trial Number (UTN)
U1111-1225-0722
Trial acronym
Linked study record
This study is not linked to any other study.

Health condition
Health condition(s) or problem(s) studied:
Immune system 310904 0
The normal menstrual cycle 311044 0
Menopause 311045 0
Condition category
Condition code
Inflammatory and Immune System 309422 309422 0 0
Normal development and function of the immune system
Reproductive Health and Childbirth 309423 309423 0 0
Menstruation and menopause

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This study will take place in the Reproductive Health Clinic of the Reproductive Biology Department Dr. Carlos Gual Castro at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (Mexico City). Daily, the investigators will check the clinical electronic records of healthy men and women assisting to the Family Planning Clinic for interview and possible recruitment, as well as, those corresponding to menopausal women assisting to Reproductive Endocrinology Clinic. The selected subjects will be invited to participate in the study after explaining all the details and procedures that will be done in this study.

The study protocol was approved by the Human Research and Ethical Committee of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, and all participants will sign an informed consent form.

Study subjects selection and study Groups
Thirty volunteer subjects without history of hormonal or any other medication, including glucocorticoids within six months before the study will be recruited and studied as follows: twenty women divided in two Groups; Group I: 10 normally ovulatory women and Group II: 10 postmenopausal women and Group III: 10 normal adult men. Those subjects in Group I will be followed longitudinally along the menstrual cycle for blood sampling (30 ml) taken as follows, days 1 to 5 (early follicular), days 10–12 (late follicular) and days 21–23 (mid-luteal) taking as day one the first day of bleeding. In the case of Groups II and III, subjects will be studied at similar time intervals. In all subjects, the blood samples will be drawn from the antecubital vein, after a 10–12 hour overnight fast (nil by mouth), between 08:00 and 09:00 h. In all subjects a medical history, physical examination, and routine screening laboratory analysis will be obtained in order to ensure good health conditions.
Intervention code [1] 313114 0
Not applicable
Comparator / control treatment
Since the aim of this study is to establish the role of ovarian hormones secreted during the normal menstrual cycle on the expression of the whole human genome in PBMC, it was decided to include as controls: women without ovarian function (menopause) and normal adult men. The comparison of these three groups will result in several contrast to be used to define the pattern of genes expression in the presence or absence of hormonal steroids.
Control group
Active

Outcomes
Primary outcome [1] 308376 0
The primary outcome will be assessed by microarray analysis of the whole human genome using RNA extracted from whole-blood PBMCs of healthy women during the early and late follicular, and the mid-luteal phases of the menstrual cycle as well as from healthy postmenopausal women and age-matched normal men.
Timepoint [1] 308376 0
Blood sampling will be performed as follows.- Group I (healthy women): at days 1 to 5 (early follicular), days 10–12 (late follicular) and days 21–23 (mid-luteal) of the menstrual cycle taking as day one the first day of menstrual bleeding. In the case of Groups II (women in menopause) and III (healthy men), the blood sampling will be performed at similar time intervals.
Primary outcome [2] 318661 0
The functional genomic analysis will be performed and the results expressed in gene ontology terms in order to identify the biological processes, cellular components and molecular functions overrepresented in each of the contrast to be studied.
Timepoint [2] 318661 0
The results of these primary outcomes are expected to be obtained at least one year after recruitment.
Primary outcome [3] 318662 0
Validation of the microarray data including expression directionality and fold change will be evaluated by real-time PCR in additional RNA samples than those used for microarray.
Timepoint [3] 318662 0
The results of these primary outcomes are expected to be obtained at least one year after recruitment and functional analysis of genomic data.
Secondary outcome [1] 365249 0
The panel of cytokines to be evaluated will depend on the results obtained by the microarray analysis in a hypothesis based manner. By the information obtained from similar studies in the literature, it is expected that the cytokines to be evaluated will be those related to a pro-inflammatory (Th1) and/or anti-inflammatory (Th2) phenotype depending of the hormonal milieu prevalent in a given phase of the menstrual cycle.
Timepoint [1] 365249 0
The results of the secondary outcome are expected to be obtained during the second year after recruitment and functional analysis of genomic data.

Eligibility
Key inclusion criteria
Group I:
-Healthy ovulatory women.
-Age: 18 to 35 years old.
-Body mass index (BMI): 18-27.5 kg/m2.
-Regular menstrual cycles between 28 to 30 days of duration.
-At least 6 months postpartum or abortion.
-Normal basal hemoglobin.
-Availability to come to all visits.
-Acceptance to participate in this study voluntarily.
-Informed consent signed.

Group II:
-Healthy women in menopause.
-Age: greater than or equal to 50 years old.
-Body mass index (BMI): 18-27.5 kg/m2
-Normal basal hemoglobin.
-Availability to come to all visits.
-Acceptance to participate in this study voluntarily.
-Informed consent signed.

Group III:
-Healthy adult men.
- Age: 18 to 35 years old.
-Body mass index (BMI): 18-27.5 kg/m2
-Normal basal hemoglobin.
-Availability to come to all visits.
-Acceptance to participate in this study voluntarily.
-Informed consent signed.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Group I: Healthy ovulatory women.
-  Pregnancy suspected or confirmed.
-  Gynecologic neoplasia.
-  Abnormal uterine bleeding.
-  Pathological galactorrhea.
-  Pelvic inflammatory disease.
-  Immune-type disease.
- Changes over 3% of the BMI registered in the first visit during the study period.
- Endocrine diseases or degenerative as diabetes mellitus, hypertension, neoplasia, deep venous thrombosis, cardiovascular disease, hepatic or kidney injury (accute or chronic).
-  Use of hormonal contraceptives, glucocorticoids, antidepressants, antiretroviral, immunemodulators or immunesuppressants, antibiotics or another treatment that could interfere with the activities of innate or acquired immunity.
-  Infectious process in the last three weeks.
- Participation in another project that could interfere with the present study.

Group II: Healthy women in menopause.
- Gynecologic neoplasia.
- Postmenopausal uterine bleeding.
- Immune-type disease.
-  Pathological galactorrhea.
- Use of hormonal therapy.
- Endocrine diseases or degenerative as diabetes mellitus, hypertension, neoplasia, deep venous thrombosis, cardiovascular disease, hepatic or kidney injury (accute or chronic).
-  Use of hormonal therapy, glucocorticoids, antidepressants, antiretroviral, immunemodulators or immunesuppressants, antibiotics or another treatment that could interfere with the activities of innate or acquired immunity.
-  Infectious process in the last three weeks.
- Participation in another project that could interfere with the present study.

Group III: Healthy adult men.
-  Testicular or prostatic neoplasia.
-  Pathological galactorrhea.
-  Immune-type disease.
- Endocrine diseases or degenerative as diabetes mellitus, hypertension, neoplasia, deep venous thrombosis, cardiovascular disease, hepatic or kidney injury (accute or chronic).
-  Use of hormonal therapy (exogenous androgens or treatment to induce spermatogenesis), glucocorticoids, antidepressants, antiretroviral, immunemodulators or immunesuppressants, antibiotics or another treatment that could interfere with the activities of innate or acquired immunity.
-  Infectious process in the last three weeks.
- Participation in another project that could interfere with the present study.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Differential gene expression will be determined using linear statistical models with arbitrary coefficients and the contrasts of interest analyzed using the Bioconductor library limma. Genes will be selected on the bases of a fold-change (FC) greater than 1.3, and a B value greater than 3.0 to identify the significant up- and down- differentially expressed genes. To get an insight into the biological processes associated with the list of differentially expressed genes, several bioinformatics platforms will be used. The adjusted p-value will be calculated by an exact Fisher test in order to evaluate the significant overrepresentation of functional terms in the list of differentially expressed transcripts. The bio-functions will be also evaluated using the Ingenuity Pathway Analysis (IPA: http://www.ingenuity.com). We will consider a canonical pathway as relevant when it fulfills both; an absolute z-score greater than 2 and a -log (p-value) greater than 1.50E00.

The inter- and intra-groups results will be analyzed with descriptive statistics by Software IBM SPSS Versión 22.0.0 and the use of parametric or non-parametric tests will depend of the type of variable distribution. Based on the homogeneity and distribution of data, Student´s t-test or non-parametric Mann-Whitney´s test will be performed for comparing the difference between Groups. The results will be expressed as the mean +/- SEM or SD as appropriate. A p-value less than or equal to 0.05 is considered as significant.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/02/2019
Actual
Date of last participant enrolment
Anticipated
1/04/2019
Actual
Date of last data collection
Anticipated
3/06/2019
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment outside Australia
Country [1] 21113 0
Mexico
State/province [1] 21113 0
Mexico City

Funding & Sponsors
Funding source category [1] 301383 0
Hospital
Name [1] 301383 0
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ)
Country [1] 301383 0
Mexico
Primary sponsor type
Hospital
Name
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ)
Address
Vasco de Quiroga 15 Belisario Domínguez, sec. XVI, 14080. Tlalpan, Mexico City.
Country
Mexico
Secondary sponsor category [1] 301052 0
None
Name [1] 301052 0
Address [1] 301052 0
Country [1] 301052 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302121 0
Ethics Committee of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Ethics committee address [1] 302121 0
Ethics committee country [1] 302121 0
Mexico
Date submitted for ethics approval [1] 302121 0
01/10/2018
Approval date [1] 302121 0
09/11/2018
Ethics approval number [1] 302121 0
Reg. Conbioética-09-CEI-011-20160627

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89186 0
Dr Marta Margarita Durand Carbajal
Address 89186 0
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Vasco de Quiroga 15 Belisario Domínguez, sec. XVI, 14080. Tlalpan, Mexico City.
Country 89186 0
Mexico
Phone 89186 0
+5215526908374
Fax 89186 0
Email 89186 0
marta.durandc@incmnsz.mx
Contact person for public queries
Name 89187 0
Marta Margarita Durand Carbajal
Address 89187 0
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Vasco de Quiroga 15 Belisario Domínguez, sec. XVI, 14080. Tlalpan, Mexico City.
Country 89187 0
Mexico
Phone 89187 0
+5215526908374
Fax 89187 0
Email 89187 0
marta.durandc@incmnsz.mx
Contact person for scientific queries
Name 89188 0
Marta Margarita Durand Carbajal
Address 89188 0
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Vasco de Quiroga 15 Belisario Domínguez, sec. XVI, 14080. Tlalpan, Mexico City.
Country 89188 0
Mexico
Phone 89188 0
+5215526908374
Fax 89188 0
Email 89188 0
marta.durandc@incmnsz.mx

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All information resulted from this study, including that corresponding to volunteers is considered as confidential. The results will be made public without subjects identification in scientific meetings and publications as stated by our Institutional review board. All this information has been registered in the informed consent form signed by all volunteers.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.