Clinical trial NCT05737329: Efficacy, Safety, and Tolerability of Higher Doses Estrogen Therapy in Women With Premature Ovarian Insufficiency
Official title: Optimization of Management Tactics for Women With Premature Ovarian Insufficiency, Taking Into Account Their Clinical and Hormonal Profile
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Primary Ovarian Insufficiency
Lead sponsor: Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare
Sponsor class: OTHER_GOV
First posted: 2023-02-21
Enrollment: 80
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Women with POI taking standard-dose estradiol hormone replacement therapy (E2/dydrogesterone (oral) (2.0/10 mg)) were invited to the study. We conducted a pilot study designed to compare the effectiveness of oral estradiol (2mg/ day) and Transdermal estradiol gel 0.1% (Gel sachet 1.0mg/ day) as standard-dose estradiol hormone replacement therapy. The obtained results on the absence of a significant difference in the effect of the above therapy made it possible to justify the prescription of higher doses of estrogens without prior switching from oral to transdermal therapy in equivalent doses in all study participants. Study participants will consistently receive Transdermal estradiol gel 0.1% (Gel sachet 1.5mg/ day) and Transdermal estradiol gel 0.1% (Gel sachet 2.0mg/ day) (both with 200mg micronized progesterone administered vaginally for 14days per cycle) with an outcome assessment at each stage of the study.
Primary purpose: TREATMENT

Brief summary: The goal of this study is to assess the effects of higher doses versus standard hormone therapy on quality of life (QoL), symptoms due to estrogen deficiency, and bone health in women with premature ovarian insufficiency (POI).

The efficacy of the hormonal treatment will be assessed clinically and also by measuring serum concentrations of Estradiol (E2), Follicle-Stimulating Hormone (FSH), Luteinizing hormone (LH), total Testosterone (T), Estrone (E1), E1 sulfate (E1S), and Sex Hormone Binding Globulin (SHBG). Bone mineral density (BMD) will be measured using dual-energy X-ray absorptiometry. Safety will be assessed by measuring endometrial thickness with Gynecological transvaginal ultrasound (TVS), treatment-related adverse events (AEs) and treatment-emergent AEs monitoring.


Eligibility criteria: Inclusion Criteria:

* Patients with karyotypically normal spontaneous POI diagnosed before the age of 40. POI as defined by: change in menstrual function (oligomenorrhea and/or amenorrhea for at least 4 months), elevated serum follicle stimulating hormone (FSH ≥ 25 IU/L with 4 to 6 weeks interval)
* Between 18-45 years of age
* Use of standard-dose estradiol HRT (Estradiol 2 mg+ Dydrogesterone10 mg) for at least the last 12 months
* Signed informed consent before inclusion in the study

Exclusion Criteria:

* Any contraindication to HRT per the current drug labels. These could include, but are not limited to: history of venous thromboembolism, estrogen-sensitive cancer history, regular cigarette smoking and history of or active liver disease, bleeding from the genital tract of unknown origin, etc.
* POI due to cytotoxic chemotherapy or radiation therapy, surgery
* Diseases that may be associated with hot flashes (such as pheochromocytoma, hyperthyroidism, medullary carcinoma of the thyroid, acromegaly, pancreatic islet-cell tumors, renal cell carcinoma, carcinoid syndrome, systemic mast cell disease, neurological flushing, emotional flushing, spinal cord injury)
* Taking medications that can also cause hot flashes (such as Tamoxifen, Raloxifene, Tricyclic antidepressants, Monoamine oxidase inhibitors, Calcium channel blockers, Depo leuprolide, Clomiphene, Serotonin uptake inhibitors)
* Severe somatic conditions (uncontrolled hypertension, kidney disease, liver disease, etc.)
* Diseases with impaired thyroid and adrenal gland function
* Refusal to participate

Primary outcomes:
measure: Evaluation of the severity of estrogen deficiency symptoms
timeFrame: 3 months
measure: Changing the assessment of quality of life using the Short Form Health Survey-36 (SF-36)
timeFrame: 3 months
measure: Changing the assessment of menopause-related quality of life measured using the Menopause-Specific Quality of Life (MENQOL) questionnaire.
timeFrame: 3 months
Secondary outcomes:
measure: Сhanges in the level of sex hormones after using higher doses estrogen therapy
timeFrame: Assessment of changes in the level of sex hormone in peripheral blood: testosterone (nmol/l). Reference values: 0,52 - 2,5 nmol/l. Blood sampling is performed at baseline and after 3 months.
measure: Сhanges in the level of sex hormones after using higher doses estrogen therapy
timeFrame: 3 months
measure: Сhanges in the level of FSH after using higher doses estrogen therapy
timeFrame: 3 months
measure: Сhanges in the level of E1 after using higher doses estrogen therapy
timeFrame: 3 months
measure: Сhanges in the level of E1S after using higher doses estrogen therapy
timeFrame: 3 months
measure: Сhanges in the level of SHBG after using higher doses estrogen therapy
timeFrame: 3 months
measure: Bone mineral density (BMD) response to using higher doses estrogen therapy for 12 Months
timeFrame: 12 Months
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare
Study officials:
affiliation: FSBI "National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov" Ministry of Healthcare of the Russian Federation
name: Victoria Averkova
role: STUDY_CHAIR
References: