Impact of Estrogen + Estradiol Receptor Alpha Modulator Therapy on Oxidative Stress in Post-menopausal Women With and Without Sleep Apnea (Alpha MenoX)

One of the most likely mechanisms explaining the sleep apnea (SA)-induced increase in metabolic syndrome is the oxidative stress (OS) induced by intermittent hypoxia (IH). There are clear-cut signs of OS in postmenopausal women that may be further enhanced by SA. In rats exposed to IH, an estradiol receptor alpha agonist decreases the level of OS markers. The aims of this study are to compare OS in apneic and non-apneic postmenopausal women and to demonstrate that OS will improve after 3 months of treatment with ER alpha agonists (Duavive) in apneic post-menopausal women.

Study Overview

• Status: Recruiting
• Conditions: Sleep Apnea; Oxidative Stress; Post Menopausal
• Intervention / Treatment: Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene)

Detailed Description

Sleep apnoea (SA) is highly prevalent in general population. It is a sex-specific respiratory disease with a lower incidence in women than in men but it increases after menopause. SA and nocturnal intermittent hypoxia (IH) predict the risks of metabolic syndrome independently of obesity, and in patients without comorbidities, SA is associated with insulin resistance. One of the most likely mechanisms explaining the SA-induced increase in metabolic syndrome is the oxidative stress (OS) induced by IH. There are clear-cut signs of OS in postmenopausal women that may be further enhanced by SA resulting in an increased activity of the sympathetic system as well as damages in adipose tissue, blood vessels, and in the liver. Estradiol is a potent antioxidant hormone. Recent experiments conducted in Dr Joseph laboratory demonstrated that in ovariectomized female rats exposed to IH, an ER alpha agonist decreases the level of "Advanced Oxidation Protein Products", prevents excessive mitochondrial ROS production, and the increase of arterial blood pressure. Oestrogens combined with a tissue-specific estradiol receptor modulators (bazedoxifene) are approved and available in Canada (Duavive) for the treatment of vasomotor symptoms and prevention of osteoporosis associated with menopause. The aims of this study are to compare OS in apneic and non-apneic postmenopausal women and to demonstrate that OS will improve after 3 months of treatment with ER alpha agonists (Duavive) in apneic post-menopausal women. 18 newly diagnosed women with untreated severe SA and 18 without SA will be recruited from the sleep clinic. Eligible subjects will be post-menopausal non-smoking women aged 30 to 65 years with a BMI less/equal to 35 kg.m-2, apnoea + hypopnea index < 15/h (non SA group) or ≥ 30/h (SA group) on a polysomnographic recording. The study will be a prospective comparative trial. Following completion of baseline measurements, subjects will receive 1 tablet of Duavive (0.45 estrogens mg and 20 mg bazedoxifene) daily for 3 months. A follow-up phone call will be completed monthly, and side effects will be recorded. All measurements will be repeated after 3 months of Duavive. The main outcome is the levels of Advanced Oxidation Protein Products and malondialdehyde as a reflect of cellular oxidative damages. The investigators will also measure plasmatic activity of superoxide dismutase and serum nitrite + nitrate levels. Secondary outcomes are related to metabolic (anthropometric variables, biologic markers of glucose homeostasis, lipid profiles, orexin-A and liver function), cardiac health (arterial blood pressure, 24-h heart rate variability to measure cardiac autonomic function) and quality of life. Analysis: Differences between results obtained in each condition will be analysed using ANOVA. Statistical significance will be considered at p<0.05. Considering the changes in OS observed with hormonal therapy in post-menopausal women and those observed with SA treatment, the sample size was determined to be able to demonstrate a 30 % difference in OS between SA and non-apneic women following 3 month of treatment with Duavive with alpha =0.05, 80% power analysis and a 20% drop-out rate. New avenues in postmenauposal hormonal therapy may have a huge impact on morbidity/mortality and a drug therapy should be more easily accepted that CPAP to reach this goal. These results should open the door to an RCT aimed at quantifying benefits of such treatment on metabolic syndrome features.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Frederic Series; Phone Number: 5513 418 656 8711; Email: frederic.series@med.ulaval.ca

Study Locations

• Canada
  • Quebec, Canada, G1V 4G5
    • Recruiting
    • IUCPQ
    • Contact: Frederic Series, MD; Phone Number: 5513 418 656 8711; Email: frederic.seriesd@med.ulaval.ca
    • Principal Investigator: Frederic Series, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• post-menopausal women
• aged 45 to 65 years
• BMI less/equal 35 kg.m-2,
• apnoea + hypopnea index (AHI) < 15/h (non SA group) or ≥ 30/h (SA group) on a polysomnographic recording,
• 90% of AHI associated with obstructive events,
• regular exercise, dietary and sleep habits
• free of sleep debt (insomnia, reported habitual sleep time > 6 h/night),
• stable medical condition.

Exclusion Criteria:

• clinically significant diurnal somnolence requiring immediate treatment in SA patients,
• nocturnal hypoventilation (% sleep time below 90% SaO2 > 10 %, PaCO2 > 45 mmHg),
• use of hormonal therapy,
• use of any medication with a respiratory depressant effect (narcotics),
• contraindication to the dug used in the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Post menopausal sleep apnea; Post menopausal women with severe sleep apnea	Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene); Drug given for 3 months in each participant
EXPERIMENTAL: Post menopausal non sleep apnea; Post menopausal women without sleep apnea	Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene); Drug given for 3 months in each participant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
oxidative stress	Advanced Oxidation Protein Products	Changes between baseline and after 3 months drug treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
glucose homeostasis	HOMA-IR	Changes between baseline and after 3 months drug treatment
total cholesterol	serum cholesterol	Changes between baseline and after 3 months drug treatment
triglycerides	serum triglycerides	Changes between baseline and after 3 months drug treatment
aspartate aminotransferase (AST)	serum aspartate aminotransferase	Changes between baseline and after 3 months drug treatment
gamma-glutamyl transferase (∂-GT)	serum gamma-glutamyl transferase	Changes between baseline and after 3 months drug treatment
Orexin-A	Orexin-A	Changes between baseline and after 3 months drug treatment
C-reactive protein	serum C-reactive protein	Changes between baseline and after 3 months drug treatment
arterial blood pressure	resting arterial blood pressure	Changes between baseline and after 3 months drug treatment
heart rate variability	24-holter	Changes between baseline and after 3 months drug treatment

Collaborators and Investigators

• Sponsor: Laval University
• Collaborators: V Joseph; C Minville; C Rheaume

Publications and helpful links

General Publications

• Laouafa S, Ribon-Demars A, Marcouiller F, Roussel D, Bairam A, Pialoux V, Joseph V. Estradiol Protects Against Cardiorespiratory Dysfunctions and Oxidative Stress in Intermittent Hypoxia. Sleep. 2017 Aug 1;40(8). doi: 10.1093/sleep/zsx104. Erratum In: Sleep. 2020 Jul 13;43(7):
• Barrera J, Chambliss KL, Ahmed M, Tanigaki K, Thompson B, McDonald JG, Mineo C, Shaul PW. Bazedoxifene and conjugated estrogen prevent diet-induced obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the reproductive tract. Am J Physiol Endocrinol Metab. 2014 Aug 1;307(3):E345-54. doi: 10.1152/ajpendo.00653.2013. Epub 2014 Jun 17.
• Xue B, Zhao Y, Johnson AK, Hay M. Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species. Am J Physiol Heart Circ Physiol. 2008 Sep;295(3):H1025-H1032. doi: 10.1152/ajpheart.00021.2008. Epub 2008 Jul 3.
• de Lima AM, Franco CM, de Castro CM, Bezerra Ade A, Ataide L Jr, Halpern A. Effects of nasal continuous positive airway pressure treatment on oxidative stress and adiponectin levels in obese patients with obstructive sleep apnea. Respiration. 2010;79(5):370-6. doi: 10.1159/000227800. Epub 2009 Jul 3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2019
• Primary Completion (ANTICIPATED): December 1, 2023
• Study Completion (ANTICIPATED): December 1, 2023

Study Registration Dates

• First Submitted: May 22, 2019
• First Submitted That Met QC Criteria: June 7, 2019
• First Posted (ACTUAL): June 10, 2019

Study Record Updates

• Last Update Posted (ACTUAL): April 8, 2022
• Last Update Submitted That Met QC Criteria: April 6, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: oxidative stress; sleep apnea; post menopausal
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Apnea; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Bone Density Conservation Agents; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Bazedoxifene; Estrogens
• Other Study ID Numbers: IUCPQ220519

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
• product manufactured in and exported from the U.S.: No