Understanding Cycles to Improve Women's Health

Official title

Understanding Socio-ecological Variation in Menstrual Cycles to Advance Female Health

Overview

Introduction: The C-HEALTH study investigates how environmental and socio-economic conditions affect women's menstrual cycles and reproductive health. Aim: To compare progesterone levels during the luteal phase among women from different socio-economic backgrounds living in rural and urban areas in southern France. Methods: This is a prospective observational study involving 320 healthy women of reproductive age. * Hormones (progesterone, estradiol) will be measured daily in saliva. * Inflammation (Protéine C Réactive: CRP) will be measured five times per cycle via blood drops. * Participants will wear a smart ring to monitor body temperature and activity. * Daily symptoms and lifestyle data will be collected. * Environmental exposures (pollution, stress, living conditions) will be assessed and linked to menstrual health outcomes.

Detailed description

Introduction:

Menstrual health is an important indicator of women's overall health, but the biological and environmental factors influencing the menstrual cycle are still poorly understood. The C-HEALTH study explores how social and ecological conditions - such as pollution, stress, socio-economic status, and living environment - affect hormonal patterns and menstrual health in women living in the Occitanie region (France).

Aim:

The primary objective is to compare luteal phase progesterone levels among women from different socio-economic backgrounds living in either rural or urban areas in the Occitanie region.

The secondary objectives are:

* To compare, according to the women's environment: levels of sex hormones (progesterone and estradiol) throughout a menstrual cycle, levels of an inflammation marker (C-reactive protein) throughout a menstrual cycle, and the description of the menstrual cycle (characteristics, possible abnormalities such as pain, abnormal bleeding, etc.). * To identify environmental factors associated with potential biological and menstrual cycle abnormalities.

Methods:

To meet the objectives of this research, 80 women aged 18-45 living in Occitanie (France) will be enrolled in each socioeconomic group at each location (4 groups: low-income urban, high-income urban, low-income rural, high-income rural; total n=320).

After the inclusion visit (visit 1) and the training visit for self-sampling (visit 2), participants will collect their biological samples and data during one observed menstrual cycle, with a follow-up visit on day 7 of the cycle (visit 3), and will complete their participation with the collection of biological samples at home (visit 4).

Biological samples (saliva and dried blood spots) will be collected no later than 30 days after the end of the collection period.

The exposome matrix will be inferred using postcode and will include data from an air pollution database (Environment Data Management System - EDMS) linked primarily to traffic, industry, stationary fuel burners, forest fires and solid fuel combustion, comfort parameters (temperature, humidity), UV, pollen count, green, grey and blue spaces, vegetation, Shannon biodiversity index, noise, water quality (pesticides, heavy metals)

At the end of this study:

* Saliva samples will be analyzed using ELISA tests to measure steroid levels. * Dried blood spot samples will be analyzed using immunoenzymatic assays to measure CRP levels, using the ELISA technique. * The exposome will be analyzed using classical statistics, clustering/PCA (Principal Component Analysis) to assess exposure profiles, and EnWAS will be used to untangle independent associations between exposure variables and menstrual cycle parameters. A series of minimally adjusted univariate analyses will be performed and exposures significant at the false discovery rate will be retained in the cluster analysis. Within each cluster, a multivariable analysis will be performed to reduce the number of variables of interest. This will allow us to identify exposome factors independently associated with menstrual health.

Interventions

• Other Self-saliva sampling
  Self-saliva samples are taken every day from D1 inclusive over 1 consecutive cycle, to measure progesterone (P4) and estradiol (E2) concentrations.
• Other Self-collection of dried blood spots
  Self-blood sampling is done 5 times during the cycle to measure protéine C-Réactive (CRP) concentrations.
• Other Wearing the connected ring
  A connected ring is worn every day of the observed cycle, while maintaining lifestyle habits, to measure daily body temperature, assess heart rate variability and resting heart rate, evaluate physical activity and energy expenditure, assess stress level, and evaluate sleep quality.
• Other Ovulation test
  An ovulation test (Ovulatest®) is carried out from day 7 until a test is positive, or until day 39 if ovulation is not detected

Primary outcome measures

• Mean Luteal Phase Salivary Progesterone [Time frame: One menstrual cycle (up to 45 days)]

Secondary outcome measures (12)

• Progesterone levels [Time frame: One menstrual cycle (up to 45 days)]
• Estradiol levels [Time frame: One menstrual cycle (up to 45 days)]
• Protéine C Réactive (CRP) levels [Time frame: Day 2, Day 7, Day of ovulation (or Day 32 if ovulation is not detected), 7 days after ovulation (or Day 39 if ovulation is not detected), 12 days after ovulation (or Day 44 if ovulation is not detected)]
• The length of cycles [Time frame: Day 0]
• Period frequency [Time frame: Day 0 and the day before the next cycle]
• Cycle regularity [Time frame: Day 0 and the day before the first day of the next cycle]
• Duration of the period [Time frame: Day 0 and the last day of menstruation (up to 45 days)]
• Flow abundance [Time frame: Day 0 and the last day of menstruation (up to 45 days)]
• Score Higham [Time frame: Day 0 and the last day of menstruation (up to Day 45)]
• Ovulation test [Time frame: Day 7 to positive test (up to Day 45) or until Day 39 if ovulation is not detected]
• Body temperature [Time frame: One menstrual cycle (up to 45 days)]
• Length of the luteal phase [Time frame: First Day of ovulation and the day before the first day of the following cycle (up to Day 45), only if ovulation is detected]

Eligibility criteria

Inclusion criteria

• Woman of childbearing age (18-39 years)
• Woman not using hormonal contraception for at least 6 months
• Woman with semi-regular menstrual cycles between 21 and 45 days inclusive
• Woman with no known history of infertility
• Woman working in the same environment (urban/rural) as her place of residence
• Knowledge of the dates of periods over the last 3 cycles
• Woman who has a freezer at -20°C

Exclusion criteria

• Diagnosis by a physician of one or more of the following comorbidities: Polycystic ovarian syndrome (PCOS), Endometriosis, Adenomyosis, Diabetes or thyroid disease, Hormone-dependent gynecological cancers (breast, endometrium, ovaries), Coagulation diseases (von Willebrand), Chronic liver failure, chronic renal failure, heart disease, autoimmune disease, Autism, Diagnosis and/or treatment for a psychiatric illness
• Chronic exposure to cocaine, amphetamine/methamphetamine, morphine or ecstasy within 30 days prior to inclusion
• Chronic exposure to THC within 7 days prior to inclusion.
• Person who is not comfortable with self-sampling (hematophobia or other)
• No access to a smartphone
• No possibility of wearing a connected ring for at least 60 days 22h/24h
• Pregnant or breastfeeding woman
• Woman who gave birth or breastfed in the 2 months before the study
• Person who moved less than 2 years before the study (does not concern participants who moved in the same environment (rural or urban, less than 20 km)
• Person unable to read French
• Failure to obtain informed consent
• Person not benefiting from a national health insurance scheme
• Person under legal protection, guardianship or curatorship
• Person participating in other research involving the human person

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Ecologic or community

Study locations

France · 1 center

• Institute of Evolutionary Science of Montpellier — Montpellier

Publications

• American Academy of Pediatrics Committee on Adolescence; American College of Obstetricians and Gynecologists Committee on Adolescent Health Care; Diaz A, Laufer MR, Breech LL. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics. 2006 Nov;118(5):2245-50. doi: 10.1542/peds.2006-2481. PMID 17079600
• Male V. COVID-19 vaccination and menstruation. Science. 2022 Nov 18;378(6621):704-706. doi: 10.1126/science.ade1051. Epub 2022 Nov 17. PMID 36395209
• Wang YX, Arvizu M, Rich-Edwards JW, Stuart JJ, Manson JE, Missmer SA, Pan A, Chavarro JE. Menstrual cycle regularity and length across the reproductive lifespan and risk of premature mortality: prospective cohort study. BMJ. 2020 Sep 30;371:m3464. doi: 10.1136/bmj.m3464. PMID 32998909
• Jasienska G, Bribiescas RG, Furberg AS, Helle S, Nunez-de la Mora A. Human reproduction and health: an evolutionary perspective. Lancet. 2017 Jul 29;390(10093):510-520. doi: 10.1016/S0140-6736(17)30573-1. Epub 2017 Jul 27. PMID 28792413
• Merklinger-Gruchala A, Jasienska G, Kapiszewska M. Effect of Air Pollution on Menstrual Cycle Length-A Prognostic Factor of Women's Reproductive Health. Int J Environ Res Public Health. 2017 Jul 20;14(7):816. doi: 10.3390/ijerph14070816. PMID 28726748
• Vitzthum VJ. The ecology and evolutionary endocrinology of reproduction in the human female. Am J Phys Anthropol. 2009;140 Suppl 49:95-136. doi: 10.1002/ajpa.21195. PMID 19890865
• Jasienska G, Ellison PT. Energetic factors and seasonal changes in ovarian function in women from rural Poland. Am J Hum Biol. 2004 Sep-Oct;16(5):563-80. doi: 10.1002/ajhb.20063. PMID 15368604
• Lorenz TK, Heiman JR, Demas GE. Testosterone and immune-reproductive tradeoffs in healthy women. Horm Behav. 2017 Feb;88:122-130. doi: 10.1016/j.yhbeh.2016.11.009. Epub 2016 Nov 17. PMID 27865788

Identifiers

NCT: NCT07037082 · RECHMPL23_0352

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗