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Trial registered on ANZCTR

Registration number

ACTRN12619000135112

Ethics application status

Approved

Date submitted

21/01/2019

Date registered

30/01/2019

Date last updated

9/04/2019

Date data sharing statement initially provided

30/01/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Sex differences in exercise induced gastrointestinal damage amongst recreational athletes: A Pilot Study

Scientific title

Sex dimorphism in exercise induced gastrointestinal damage amongst recreational athletes: A Pilot Study

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1227-1618

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Intestinal damage

Menstruation

Condition category

Condition code

Oral and Gastrointestinal

Normal oral and gastrointestinal development and function

Reproductive Health and Childbirth

Menstruation and menopause

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Intervention 1: Exercise. We will be exploring the effect of exercise (the intervention) on gut damage during the menstrual cycle.

There will be three groups of participants recruited:
1. Males
2. Females with a regular, natural menstrual cycle
3. Females with a regular cycle using a hormonal contraceptive

Participants will run on a treadmill in a climate controlled room (~21 deg c, 40% relative humidity) at the University of Tasmania Newnham Campus.
There will be 3 x 1 hour sessions for all participants. They will run at a continuous effort of 70% of VO2max.
Sessions for males will be 1 x per week on the same day at the same time each week.
Sessions for females will be in accordance with their menstrual cycle, but approximately on days 1-4 (early follicular), day 11-14 (late follicular) and day 21-25 (mid luteal). Each trial for females will be at the same time of day.
Only one participant will be tested at a time.

Intervention 2: Sugar solution. Participants will ingest a sugar solution that will be used to identify gut permeability during exercise (intervention 1).
5 g lactulose and 5 g L-rhamnose will be dissolved in 150 ml tap water and ingested by the participant 5 minutes prior to the start of each exercise trial.

The interventions will be delivered by the research team, all of whom are university researchers and exercise professionals.

Intervention code [1]

Lifestyle

Comparator / control treatment

Comparisons are being made between three different participant groups: females with a natural menstrual cycle, females on hormonal contraceptives and males.

The participants will act as their own controls, but males also act as a control since they do not have a menstrual cycle.

Control group

Active

Outcomes

Primary outcome [1]

A difference in post-exercise plasma I-FABP concentration at the different timepoints and betwen males and females

Plasma I-FABP concentration will be analysed via ELISA

Timepoint [1]

Pre- and Post exercise blood samples will be taken at every trial for analysis.
Pre-exercise blood samples will be taken within 10 minutes prior to the sugar intervention and 15 minutes prior to the exercise intervention
Post-exercise samples will be taken immediately upon cessation of the exercise trial (and therefore approx 65 minutes post-sugar intervention)
Timepoints of trials are:
Males: 1 x per week for three weeks on the same day at the same time each week.
Females: in accordance with their menstrual cycle, but approximately on days 1-4 (early follicular), day 11-14 (late follicular) and day 21-25 (mid luteal). Each trial for females will be at the same time of day.

Because the groups are being compared throughout the phases of the menstrual cycle, the timepoints are pre- and post- exercise for 3 trials in accordance with the schedule noted above

Secondary outcome [1]

Indications of intestinal permeability as defined by the lactulose/rhamnose ratio via a plasma assay

Timepoint [1]

Pre- and Post exercise blood samples will be taken at every trial for analysis.
Pre-exercise blood samples will be taken within 10 minutes prior to the sugar intervention and 15 minutes prior to the exercise intervention
Post-exercise samples will be taken immediately upon cessation of the exercise trial (and therefore approx 65 minutes post-sugar intervention)
Timepoints of trials are:
Males: 1 x per week for 3 weeks on the same day at the same time each week.
Females: in accordance with their menstrual cycle, but approximately on days 1-4 (early follicular), day 11-14 (late follicular) and day 21-25 (mid luteal). Each trial for females will be at the same time of day.

Secondary outcome [2]

Oestrogen concentrations will be analysed using serum ELISA to verify the menstrual cycle phase

Timepoint [2]

Pre- and Post exercise blood samples will be taken at every trial for analysis.
Pre-exercise blood samples will be taken within 10 minutes prior to the sugar intervention and 15 minutes prior to the sugar intervention
Post-exercise samples will be taken immediately upon cessation of the exercise trial (and therefore approx 65 minutes post-sugar intervention)
Timepoints of trials are:
Males: 1 x per week on the same day at the same time each week.
Females: in accordance with their menstrual cycle, but approximately on days 1-4 (early follicular), day 11-14 (late follicular) and day 21-25 (mid luteal). Each trial for females will be at the same time of day.

Secondary outcome [3]

Progesterone concentrations will be analysed via serum ELISA to verify menstrual cycle phase

Timepoint [3]

Pre- and Post exercise blood samples will be taken at every trial for analysis.
Pre-exercise blood samples will be taken within 10 minutes prior to the sugar intervention and 15 minutes prior to the sugar intervention
Post-exercise samples will be taken immediately upon cessation of the exercise trial (and therefore approx 65 minutes post-sugar intervention)
Timepoints of trials are:
Males: 1 x per week for three weeks on the same day at the same time each week
Females: in accordance with their menstrual cycle, but approximately on days 1-4 (early follicular), day 11-14 (late follicular) and day 21-25 (mid luteal). Each trial for females will be at the same time of day.

Eligibility

Key inclusion criteria

• Trained (recreational athletes), currently training a minimum of 5 hours a week (female and male)
• Self-reported regular menstrual cycles with no history of dysfunction (females only)
• BMI within healthy range (female and male)
• Able to run on a treadmill for an hour (female and male)
• Natural cycle: have not taken hormonal contraceptives for at least 6 months and self-reported menstrual cycle is regular (24-35 days) (females only)
OR
• hormonal contraceptive: : have consistently taken a hormonal contraceptive for at least 6 months (females only)

Minimum age

18 Years

Maximum age

50 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Prior to data collection
• Amenorrhea or irregular cycles
• HC used to manage menstrual dysfunction
• History of gastrointestinal disease/injury
• BMI below 18
Post-collection of data
• Anovulation
• Hormone levels not meeting appropriate reference levels

Study design

Purpose of the study

Prevention

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Phase

Not Applicable

Type of endpoint/s

Statistical methods / analysis

There are no human studies that have investigated the relationship between gut damage and oestrogen concentrations, however both mouse models (Ricardo-da-Silva et al. 2017) and in vitro studies (Diebel et al. 2015) have shown that damage to cells from ischemic-reperfusion insults can be halved with the application of oestrogen concentrations. The oestrogen concentrations in these studies are higher than would be found in humans, however, we hypothesise that the magnitude of change in oestrogen concentrations between the early follicular and late follicular phases of the menstrual cycle could reduce damage by 15%.
Therefore, based on a post-exercise I-FABP concentrations of 615 pg·ml-1 during the early follicular phase (Van Wijck et al. 2011) and 522 pg·ml-1 during the late follicular phase (85%) and using a standard deviation of 118 pg·ml-1 and a standard alpha (0.05) and beta value (0.8), a sample size of n=13 per group was calculated. Participant numbers are also in accordance with sufficient statistical power to detect a meaningful difference in hormone concentrations across the menstrual cycle (Oosthuyse et al. 2005).

Differences between the early follicular and late follicular phases will be compared using a repeated measures ANOVA (time: pre and post-exercise x menstrual cycle phase). Group (male, female and female oral contraceptive users) x time (pre and post-exercise) main effects and interaction will be analysed using repeated measures ANOVA. If required, more complex analyses to identify interactions between and within groups will include linear regression modelling.
Participants with hormone concentration data that does not meet the criteria for specific menstrual phases will have their data excluded from analysis.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/05/2019

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

TAS

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Tasmania

Address [1]

University of Tasmania
Newnham campus
Private Bag 1345
Launceston TASMANIA 7001
AUSTRALIA

Country [1]

Australia

Primary sponsor type

University

Name

University of Tasmania

Address

University of Tasmania
Newnham campus
Private Bag 1345
Launceston TASMANIA 7001
AUSTRALIA

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Tasmania Health and Medical Human Research Ethics Committee

Ethics committee address [1]

Office of Research Services, University of Tasmania, Private Bag 1, Hobart, TAS, 7001

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

09/10/2018

Approval date [1]

27/03/2019

Ethics approval number [1]

H0017613

Summary

Brief summary

Females experience fluctuating steroid hormone profiles throughout their menstrual cycle. During the early follicular (EF) phase, characterised by the onset of bleeding, concentrations of both oestrogen and progesterone are low. Oestrogen increases, and then peaks in the late follicular (LF) phase just prior to ovulation before dropping and then increasing again during the mid-luteal (ML) phase (although not to the same concentrations as seen in the LF phase). Progesterone increases after ovulation, peaking during the ML phase and then decreasing prior to the next EF phase.

There is some evidence that females tolerate gut ischemia (i.e. a lack of oxygen in the gut, often due to blood loss in circumstances such as trauma) better than males. It has been suggested that this is attributable to the protective effects of oestrogen. Interestingly, endurance exercise also causes reduced blood flow (and therefore oxygen) to the gut because blood is redistributed to the working muscles.  After an hour of running at 70% of VO2 max blood flow has been shown to be reduced by 80% causing small intestinal injury similar to that induced by trauma. However, to date no study has looked at the menstrual cycle in humans in relation to changes in gut integrity in response to exercise.

The aim of this study is to provide preliminary data on the potential sex dimorphism in susceptibility to intestinal damage during endurance exercise, and if this damage is menstrual cycle dependent. If differences are found, this may have implications for female athletes training and racing during different phases of their menstrual cycle.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Cecilia Kitic

Address

University of Tasmania
Newnham campus
Private Bag 1345
Launceston TASMANIA 7001
AUSTRALIA

Country

Australia

Phone

+61 3 6324 5484

Fax

[email protected]

Contact person for public queries

Name

Cecilia Kitic

Address

University of Tasmania
Newnham campus
Private Bag 1345
Launceston TASMANIA 7001
AUSTRALIA

Country

Australia

Phone

+61 3 6324 5484

Fax

[email protected]

Contact person for scientific queries

Name

Cecilia Kitic

Address

University of Tasmania
Newnham campus
Private Bag 1345
Launceston TASMANIA 7001
AUSTRALIA

Country

Australia

Phone

+61 3 6324 5484

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

De-identified individual participant data underlying published results only

When will data be available (start and end dates)?

Immediately following publication, no end date determined

Available to whom?

Case-by-case basis at the discretion of Primary Sponsor

Available for what types of analyses?

meta-analyses

How or where can data be obtained?

Access will be subject to approvals by Principal Investigator

What supporting documents are/will be available?

Current supporting documents:

Updated to:

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
23720	Study protocol			[email protected]
23721	Ethical approval			[email protected]

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.

Trial Review

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