Ventricular Repolarization in Patients With Premature Ovarian Insufficiency (QTIOP)

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.

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.

Inclusion Criteria:

Patients with POI

• Patient aged 18 to 41 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)