Female Sex Hormones, Insulin Resistance and Effects of Exercise in a Human Experimental Model of Menopause

The main objective of this study is to investigate the role of female sex hormones in relation to insulin resistance in a controlled human experimental model of menopause and to explore whether exercise and/or hormone treatment (HT) can compensate for loss of endogenous sex hormone production by maintaining insulin sensitivity and metabolic activity at a level equivalent to what is seen in premenopausal women.

Loss of ovarian function is associated with an increased incidence of metabolic disease including metabolic syndrome, type 2 diabetes and cardiovascular disease. This increased disease incidence seems to be related to changes in body composition including decreased skeletal muscle mass and increased visceral fat mass as well as decreased whole body fat oxidation and energy expenditure. Regular physical activity decreases general mortality among other things by increasing fat free mass and insulin sensitivity and hereby prevents metabolic syndrome and cardiovascular disease - conditions seen with an increased incidence after menopause and could therefore be a possible treatment.

In the present study the Investigators will assess the role of sex hormones in a model of menopause where healthy women are undergoing planned bilateral oophorectomy due to risk of hereditary ovary cancer. The use of this model makes it possible to control the time point for loss of ovarian function and hereby investigate the timeframe and possible contributing factors in a strictly controlled model. 48 premenopausal women will be included in the study. The study is conducted in women who have already been offered surgical oophorectomy. The first 2 months the study will be an observational cohort study. Hereafter the patients will be allocated to one of four groups (n=12) in a randomized controlled trial, addressing the effects of 6 months of exercise with or without HT. Type of surgery has been decided before inclusion based on medical indications. The women will be offered HT according to national guidelines, but the choice is up to them. Randomization applies only to the training intervention.

Firstly the Investigators aim at investigating the role of endogenous female sex hormones and HT in relation to insulin resistance, whole body fat oxidation and -energy expenditure, changes in visceral fat mass and fat free mass after oophorectomy. Secondly, the Investigators wish to study the molecular mechanisms behind the oophorectomy-induced insulin resistance with a focus on insulin signaling in skeletal muscle and fat tissue. Lastly, the investigators aim to explore whether exercise and/or HT can compensate for loss of endogenous female sex hormone production by maintaining IS and metabolic activity, hereby preventing future incidents of metabolic disease in relation to menopause.

All in all, this project will contribute with new knowledge concerning the question of how endogenous female sex hormones affect insulin sensitivity and metabolic functioning and how exercise may be used as a disease preventive modality for middle-aged women.

Study Overview

• Status: Unknown
• Conditions: Metabolic Syndrome
• Intervention / Treatment: Behavioral: exercise; Drug: Hormone treatment

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Julie Abildgaard, MD; Phone Number: +4535457190; Email: julieabild@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• women
• going through oophorectomy to prevent hereditary cancer
• premenopausal

Exclusion Criteria:

• infection during the last month
• chronic disease
• smoking
• alcohol > 14 servings/week
• hysterectomized
• premature menopause
• BMI > 30

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: training + HT	Behavioral: exercise; The exercise intervention will conduct the following training program 4 days/week for 6 months: endurance training consisting of supervised training on a bike ergometer for 20 min at 70% of maximal heart rate (HR) the first week, increased by 5 min each week until reaching 40 min. Then the intensity will be increased to 80% of max HR over the next month and recalculated every month.; Drug: Hormone treatment; Continually estradiol and gestagens - tablets and patches or cyclic estradiol and gestagens - tablets or patches. Including: Drospirenon, Norethisteronacetat, Medroxyprogesteronacetat
Experimental: training - HT	Behavioral: exercise; The exercise intervention will conduct the following training program 4 days/week for 6 months: endurance training consisting of supervised training on a bike ergometer for 20 min at 70% of maximal heart rate (HR) the first week, increased by 5 min each week until reaching 40 min. Then the intensity will be increased to 80% of max HR over the next month and recalculated every month.
Placebo Comparator: -training + HT	Drug: Hormone treatment; Continually estradiol and gestagens - tablets and patches or cyclic estradiol and gestagens - tablets or patches. Including: Drospirenon, Norethisteronacetat, Medroxyprogesteronacetat
No Intervention: - training - HT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin sensitivity	Measured by a hyperinsulinemic euglycemic clamp as AUC for glucose infusion rate	1 year

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Julie Abildgaard, MD, Centre of Inflammation and Metabolism

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Anticipated): August 1, 2018
• Study Completion (Anticipated): August 1, 2018

Study Registration Dates

• First Submitted: July 29, 2015
• First Submitted That Met QC Criteria: August 14, 2015
• First Posted (Estimate): August 17, 2015

Study Record Updates

• Last Update Posted (Estimate): August 17, 2015
• Last Update Submitted That Met QC Criteria: August 14, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Metabolic Syndrome; Insulin Resistance; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones
• Other Study ID Numbers: H-15008066