Ventricular Repolarization in Patients With Premature Ovarian Insufficiency (QT-IOP) (QT-IOP)

Study of Ventricular Repolarization in Patients With Premature Ovarian Insufficiency and Influence of Estrogen-progestin Replacement Therapy

Ventricular repolarization, measured by corrected QT interval (QTc), is influenced by sex hormones. A QTc above 460msec predisposes to the risk of "torsades-de-pointes"(TdP). The investigators have recently shown that estradiol determines an increase in QTc elongation and progesterone shortens it. In addition, high gonadotropin levels (FSH or LH) are associated with QTc prolongation. Hypergonadotropic hypogonadisms (low progesterone and high gonadotropins) are therefore hormonal situations that promote QTc prolongation. Premature ovarian insufficiency (POI) is one of them. Its management is based on the prescription of hormone replacement therapy (HRT). Epidemiological studies have shown that these patients would be at increased risk of cardiovascular mortality. Our team is interested in the effect of this pathological hormonal situation and its HRT on ventricular repolarization in order to define whether this is a population at risk for long QTc.

Study Overview

• Status: Recruiting
• Conditions: Premature Ovarian Insufficiency
• Intervention / Treatment: Drug: Hormone replacement therapy:effect on ventricular repolarization; Diagnostic test: ECG

Detailed Description

Ventricular repolarization, measured by the duration of the heart rate corrected QT interval (QTc), is influenced by sex hormones. A QTc above 460msec predisposes to the risk of torsades-de-pointes (TdP); ventricular arrhythmias that can lead to sudden death.

From puberty to menopause, QTc is longer in women than in men (~10-15msec difference) and varies in women according to the menstrual cycle (~5-10msec). This explains the increased risk of TdP in women compared to men. During the menstrual cycle, the risk is highest for women during the follicular phase compared to the luteal phase. The investigators have recently shown that estradiol determines an increase in QTc elongation and progesterone shortens it. In addition, high gonadotropin levels (FSH or LH) are associated with QTc prolongation. Hypergonadotropic hypogonadisms (low progesterone and high gonadotropins) are therefore hormonal situations that promote QTc prolongation.

Premature ovarian insufficiency (POI) affects 1% of women under 40 years of age and is characterized by hypergonadotropic hypogonadism. POI is associated with hormonal deficiencies responsible for amenorrhea and infertility. Management is based on the prescription of hormone replacement therapy (HRT). Epidemiological studies have shown that these patients would be at increased risk of cardiovascular mortality. HRT will be based on the combination of an estrogen and a progestin and will lead to a variable decrease in gonadotropins, depending on the steroid hormones/doses used. Our team, after structuring one of the largest international cohorts of patients with POI, is interested in the effect of this pathological hormonal situation and its HRT on ventricular repolarization to define whether this is a population at risk for long QTc. Indeed, ECG follow-up is recommended and many drugs (cardiovascular or not), are to be avoided, or even contraindicated in situations at risk of long QTc.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne Bissery, MD; Phone Number: +33 1 42 16 24 32; Email: anne.bissery@aphp.fr
• Study Contact Backup: Name: Fredy Pene, Mr; Phone Number: +33 1 42 16 24 35; Email: fredy.pene@aphp.fr

Study Locations

• France
  • Bordeaux, France
    • Active, not recruiting
    • Hopital Haut Leveque
  • Paris, France, 75013
    • Recruiting
    • BACHELOT
    • Contact: BACHELOT Anne, Pr; Phone Number: 01 42 16 02 46; Email: anne.bachelot@aphp.fr
    • Contact: DULON Jérôme; Phone Number: 01 42 16 02 11; Email: jerome.dulon@aphp.fr
  • Paris, France, 75013
    • Recruiting
    • Pitie Salpetriere
    • Contact: SALEM Joe Elie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Patients with POI

• Patient aged 18 to 40 years
• Patient with POI diagnostic criteria (FSH >25UI/l twice at intervals of a few weeks) with amenorrhea
• No hormone treatment interacting with the gonadotropic axis for at least one month before inclusion
• Patient who has signed informed consent
• Patient affiliated to a social security system

Healthy volunteers (including POI control group)

• Healthy women, aged 18 to 40 years, age-matched (+/- 5 years), and by BMI class (BMI<18, 18-25, 25-30, 30-35, 35-40, >40) compared to women with BPI
• Women with regular cycles of 26 to 32 days
• Women who has signed an informed consent form
• Patient affiliated to a social security system

Exclusion Criteria:

Patients with POI

• Patient on HRT during the 1st evaluation
• Pregnant or breastfeeding woman
• Treatment regimen known to lengthen QT or act on ventricular repolarization
• Cardiac history in particular cardiac rhythm disorder
• Diabetes
• Patient on AME (unless derogation from affiliation),
• Severe renal insufficiency (MDRD <30ml/min/m²)

Healthy volunteers (including POI control group)

• Diabetes or any chronic disease (including cardiovascular and endocrine)
• Pregnant or breastfeeding woman
• Hormonal contraceptive treatment in progress or stopped less than 3 months ago
• Chronic treatment affecting the duration of QTc
• Woman under AME (unless affiliation derogation)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Premature ovarian insufficiency; 60 patients with POI followed in the endocrinology department	Drug: Hormone replacement therapy:effect on ventricular repolarization; Hormone replacement therapy and QTc measurement
Other: healthy volunteers; 60 healthy volunteers matched with POI's patients	Diagnostic test: ECG; QTc measurement

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of QTc	Compare the duration of QTc in patients with non-substituted POI with that of matched healthy volunteers on cardiovascular risk factors. The QTc will be measured by the Fridericia method	in the luteal phase between Day22 and Day25

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of QTc	Measure the duration of QTc in women with POI before and after the introduction of HRT	the day before and between Day22 and Day60 after the introduction of HRT
Duration of QTc	Study the association between sex hormone levels (gonadotropins, steroid hormones) and QTc duration, as well as their variation in patients with POI and healthy volunteers	in the luteal phase between Day22 and Day25

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Anne BACHELOT, Pr, Assistance Publique - Hôpitaux de Paris; Study Director: Joe Elie Salem, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2021
• Primary Completion (Estimated): April 13, 2024
• Study Completion (Estimated): April 13, 2024

Study Registration Dates

• First Submitted: September 26, 2019
• First Submitted That Met QC Criteria: November 15, 2019
• First Posted (Actual): November 18, 2019

Study Record Updates

• Last Update Posted (Actual): January 9, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: QTc; Hormone replacement therapy; Premature ovarian insufficiency; Torsade de pointe
• Additional Relevant MeSH Terms: Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Premature Birth; Primary Ovarian Insufficiency; Menopause, Premature; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones
• Other Study ID Numbers: APHP180160; 2019-A01002-55 (Registry Identifier: IDRCB)

Drug and device information, study documents

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