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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Recruiting

CT.gov ID

NCT04167033

Collaborator

(none)

120

Enrollment

Location

Arms

37.9

Anticipated Duration (Months)

3.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Premature Ovarian Insufficiency	Drug: Hormone replacement therapy:effect on ventricular repolarization Diagnostic Test: ECG	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This is a bicentric case-control study: 60 patients with POI followed in the endocrinology department, and 60 healthy volunteers matched with POI's patients on age (+/- 5 years), on BMI classes (BMI<18, 18-25, 25-30, 30-35, 35-40, >40) and with regular cycles (26 to 32 days).This is a bicentric case-control study: 60 patients with POI followed in the endocrinology department, and 60 healthy volunteers matched with POI's patients on age (+/- 5 years), on BMI classes (BMI<18, 18-25, 25-30, 30-35, 35-40, >40) and with regular cycles (26 to 32 days).

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Apr 14, 2021

Anticipated Primary Completion Date :

Dec 15, 2023

Anticipated Study Completion Date :

Jun 12, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Duration of QTc [in the luteal phase between Day22 and Day25]
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

Secondary Outcome Measures

Duration of QTc [the day before and between Day22 and Day60 after the introduction of HRT]
Measure the duration of QTc in women with POI before and after the introduction of HRT
Duration of QTc [in the luteal phase between Day22 and Day25]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	BACHELOT	Paris		France	75013

Sponsors and Collaborators

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