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.

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