Does Estrogen Blunt the Effects of Exercise Training on Glycemic Control

The Impact of 17beta-estradiol Treatment on Insulin Sensitivity, Immune Function, Inflammation and Skeletal Muscle Metabolism Following Exercise Training in Sedentary, Overweight Males

Previous research has found that males and females respond differently to exercise training, particularly with respect to improvements in blood sugar control and immune system health. This is crucial since insulin resistance, which can lead to type 2 diabetes and other health problems, affects millions of Canadians. People with insulin resistance often have higher inflammation. Exercise is known to improve insulin resistance and reduce inflammation, but females seem to benefit less from exercise compared to men. The investigators believe this difference might be due to estrogen, a hormone that helps regulate blood sugar (in non-exercising conditions) and reduce inflammation. Females have higher estrogen levels, which might explain their ability to regulate resting blood sugar control and also immune function at rest. Our research will investigate how estrogen influences the acute and chronic effects of exercise males. The investigators will study how estrogen influence's the body's response to exercise, particularly in terms of reducing inflammation and improving blood sugar levels as well as immune function. Overweight and obese males will undergo 2 weeks of high intensity interval training while taking either an estrogen supplement or placebo. Prior to and following training males will undergo an assessment of maximal fitness (VO2max test) and an oral glucose tolerance test. Prior to and following the acute exercise test blood samples will be taken to determine the acute effects of exercise on immune cell function and inflammation. Prior to and during the oral glucose tolerance test participants will have blood samples taken to determine glucose handling and insulin sensitivity. They will also have a muscle biopsy taken prior to and 1h into the oral glucose tolerance test to determine the effects of estrogen supplementation on insulin signaling, mitochondrial content and function, fat metabolism and fat storage in skeletal muscle.

Study Overview

• Status: Not yet recruiting
• Conditions: To Determine Whether Estrogen Influences the Effects of Training on Glycemic Control and Insulin Sensitivity
• Intervention / Treatment: Other: EXERCISE TRAINING WITH OR WITHOUT MEDICATION

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Vito Pipitone, PhD Candidate; Phone Number: 519-888-4567; Email: vito.pipitone@uwaterloo.ca

Study Locations

• Canada
  • Ontario
    • Waterloo, Ontario, Canada, N2L 3G1
      • University of Waterloo
      • Contact: Vito Pipitone, PhD Candidate; Phone Number: 519-888-4567; Email: vito.pipitone@uwaterloo.ca
      • Principal Investigator: Michaela Devries-Aboud, PhD
      • Sub-Investigator: Vito Pipitone, PhD Candidate
      • Sub-Investigator: Emma Dare, PhD
      • Sub-Investigator: Madeline Noble, MSc
      • Sub-Investigator: Sean Gartner, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Biological males (with no previous hormonal supplementation).
• Between the ages of 18-35 years old
• Non-smokers
• Sedentary individuals (i.e., engaging in intentional moderate-to-vigorous physical activity <2x/week)
• Body mass index 27-32 kg/m2
• Body fat % > 22%

Exclusion Criteria:

1. Any state that can impact the hormonal milieu (e.g., drug/hormonal supplementation related to health).
2. Usage of anti-inflammatory medications, >1 glucose lowering medications, insulin, platelet inhibitors, anti-coagulant medications or simvastatin, beta-blockers, weight loss medications (Orlistat, Saxenda, Contrave, Ozempic) or any medications known to affect protein metabolism (i.e., corticosteroids).
3. Presence of cardiovascular, respiratory, metabolic, autoimmune or renal disease.
4. Presence of any condition that makes the participant unable to participate in physical activity as determined using the CSEP Get Active Questionnaire.
5. Presence of injury that restricts exercise performance.
6. VO2max > 50th percentile for age.
7. Previous (within the last 2 months) or current use of ergogenic aids (i.e. creatine).
8. Previous or current use of weight loss medications, including liraglutide, semaglutide, orlistat, ozempic, etc.
9. History and/or diagnosis of blood clots or family history of blood clot disorders.
10. History of allergies or sensitivities to local anesthetic
11. Ophthalmic vascular disease
12. Classical migraines
13. History of thromboembolic disease
14. Consume 15 or more alcoholic drinks/week or 3 drinks per day
15. Bleeding disorders
16. Severe peripheral neuropathy
17. Muscular dystrophy
18. Prior bariatric surgery
19. Osteoporosis/osteopenia
20. Orthopaedic issues
21. Presence of GI disorders (i.e., Colitis, Crohns disease, Celiac disease)
22. Presence of liver disease or dysfunction (i.e., diagnosed NAFLD, NASH, cirrhosis, previous liver transplant)
23. History of cancer
24. Type 1 or 2 diabetes
25. Presence of renal disorders (creatinine > 140)
26. Uncontrolled hypertension (>140/90 mmHg)
27. History of allergies or sensitivities to estradiol or to any ingredient in the formulation or component of the container
28. History and/or diagnosis of blood clots or family history of blood clot disorders
29. Have an implantable electronic device
30. Medical psychiatric history of depression, bipolar, anxiety, suicidal ideation, etc.
31. Inherited clotting disorders
32. Chest pain or shortness of breath
33. Inflammatory disorders (e.g., inflammatory bowel disorder)
34. Significant weight loss in the 3-month period prior to the study (10% of total body weight)
35. Any kind of major surgery recently
36. Bleeding disorders
37. Active or history of thromboembolic disease (including confirmed venous thromboembolism)
38. Ophthalmic vascular disease
39. Classical migraines

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Estrogen; 1mg/d 17-beta estradiol x 2 day and 2mg/d 17-beta estradiol for 14 days	Other: EXERCISE TRAINING WITH OR WITHOUT MEDICATION; 2 weeks of high intensity interval training while either taking estrogen or placebo
Placebo Comparator: Placebo; 400mg/d of glucose polymer x 16 days	Other: EXERCISE TRAINING WITH OR WITHOUT MEDICATION; 2 weeks of high intensity interval training while either taking estrogen or placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose AUC	Glucose AUC determined from blood samples taken during a 2h oral glucose tolerance test	Visit 3 (baseline) and Visit 11 (Day 16)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin resistance/sensitivity	at rest (HOMA-IR) and during a 2 h oral glucose tolerance test (Matsuda index)	Visit 3 (baseline) and Visit 11 (Day 16)
Markers of insulin signaling	Western blot of the following markers: AMPKα Thr172 & total AMPKα; phosphorylated Akt Ser437 & total Akt; phosphorylated TBC1D4 Thr642 & total TBC1D4; phosphorylated TBC1D1 Ser237 & total TBC1D; total GLUT4 in human skeletal muscle in the fasted and insulin stimulated state	Visit 3 (baseline) and Visit 11 (Day 16)
Membrane bound GLUT4	GLUT4 content at the membrane in the fasted and insulin stimulated state (determined via immunofluorescence)	Visit 3 (baseline) and Visit 11 (Day 16)
Peripheral blood mononuclear cells	determination of immune cell response to acute exercise	Visit 2 (baseline) and Visit 10 (Day 14)
Plasma cytokines from isolated PBMCs	pro- and anti-inflammatory cytokine content will be determine using a cytokine array and commercially available kits	Visit 2 (baseline) and Visit 10 (Day 14)
Mitochondrial content	determined using electron microscopy	Visit 3 (baseline) and Visit 11 (Day 16)
Mitochondrial respiration	skeletal muscle mitochondrial respiration determined using high-resolution respirometry	Visit 3 (baseline) and Visit 11 (Day 16)
intramyocellular lipid (IMCL) content	total and subcellular location-specific content and storage characteristics	Visit 3 (baseline) and Visit 11 (Day 16)
aerobic fitness (VO2max)	VO2max determined during a graded exercise test	Visit 2 (baseline) and Visit 10 (Day 14)
Sex hormone concentrations	Serum estradiol measured using commercially available kits	Visit 3 (baseline) and Visit 11 (Day 16)
Serum hormone concentrations	Serum progesterone measured using commercially available kits	Visit 3 (baseline) and Visit 11 (Day 16)
Sex hormone concentrations	Serum testosterone measured using commercially available kits	Visit 3 (baseline) and Visit 11 (day 16)
Serum hormone concentrations	Serum growth hormone measured using commercially available kits prior to a maximal graded exercise test and immediately (t=0 min), 30 and 60 min after the graded exercise test.	Visit 2 (baseline) and visit 10 (day 14)
Serum hormone concentrations	Serum glucagon measured using commercially available kits prior to a maximal graded exercise test and immediately (t=0 min), 30 and 60 min after the graded exercise test.	Visit 2 (baseline) and visit 10 (Day 14)
Neurotransmitter concentration	Serum epinephrine concentration measured using a commercially available kit prior to a maximal graded exercise test and immediately (t=0 min), 30 and 60 min after the graded exercise test.	Visit 2 (baseline) and Visit 10 (day 14)

Collaborators and Investigators

• Sponsor: University of Waterloo
• Investigators: Principal Investigator: Michaela Devries, PhD, University of Waterloo

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: August 14, 2026
• First Submitted That Met QC Criteria: August 25, 2026
• First Posted (Actual): August 27, 2026

Study Record Updates

• Last Update Posted (Actual): August 27, 2026
• Last Update Submitted That Met QC Criteria: August 25, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: estrogen; insulin sensitivity; exercise training; glycemic control
• Additional Relevant MeSH Terms: Metabolic Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Nutritional and Metabolic Diseases; Insulin Resistance; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Pharmaceutical Preparations; Investigative Techniques; Technology, Pharmaceutical; Exercise; Dosage Forms
• Other Study ID Numbers: 46726

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No