Efficacy, Safety, and Tolerability of Higher Doses Estrogen Therapy in Women With Premature Ovarian Insufficiency

Study Overview
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Brief Summary
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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.

Official Title
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Optimization of Management Tactics for Women With Premature Ovarian Insufficiency, Taking Into Account Their Clinical and Hormonal Profile

Conditions
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Primary Ovarian Insufficiency

Intervention / Treatment
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* Drug: Transdermal estradiol gel 0.1% 1.5mg/ day
* Drug: Transdermal estradiol gel 0.1% 2.0mg/ day


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Transdermal estradiol gel 0.1% 1.5mg/ day<br>Patient will be given Hormone Replacement Therapy (HRT) in the form of: Transdermal estradiol gel 0.1% 1.5mg (Gel sachet) in continuous daily regimen. The progesterone component of HRT (200mg micronized progesterone administered vaginally) will be given for 14 days, starting from day 14 through day 28 of each cycle. | Drug: Transdermal estradiol gel 0.1% 1.5mg/ day<br>* Estradiol gel 0.1% 1.5mg/ daily + Micronized Progesterone 200mg<br>Drug: Transdermal estradiol gel 0.1% 2.0mg/ day<br>* Estradiol gel 0.1% 2.0mg/ daily + Micronized Progesterone 200mg<br>|
| Other: Transdermal estradiol gel 0.1% 2.0mg/ day<br>Patient with insufficient effect from previous treatment estradiol gel 0.1% 1.5mg will be given HRT in the form of: Transdermal estradiol gel 0.1% 2.0mg (Gel sachet) in continuous daily regimen. The progesterone component of HRT (200mg micronized progesterone administered vaginally) will be given for 14 days, starting from day 14 through day 28 of each cycle. | Drug: Transdermal estradiol gel 0.1% 1.5mg/ day<br>* Estradiol gel 0.1% 1.5mg/ daily + Micronized Progesterone 200mg<br>Drug: Transdermal estradiol gel 0.1% 2.0mg/ day<br>* Estradiol gel 0.1% 2.0mg/ daily + Micronized Progesterone 200mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the severity of estrogen deficiency symptoms | The Green scale questionnaire was used initially and after 3 months against the background of HRT. The questionnaire includes 21 questions from 0 to 3 points, where a lower score means a better result. | 3 months | 
| Changing the assessment of quality of life using the Short Form Health Survey-36 (SF-36) | The SF-36 is a generic QoL instrument. It consists of 36 items organized into eight domains: Physical Function (AF), Physical Role Function (RF), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Function (SF), Emotional Role Function (RE), and Mental Health (SM) as well as an item on the change of General Health. The scores of each domain have been converted into a scale from 0 to 100. Lower scores are indicative of worse conditions. | 3 months | 
| Changing the assessment of menopause-related quality of life measured using the Menopause-Specific Quality of Life (MENQOL) questionnaire. | The MENQOL questionnaire is a self-administered instrument. This validated questionnaire (range 1-8) assesses four quality of life domains; physical (16 items), vasomotor (3 items), psychosocial (7 items) and sexual (3 items). Scoring generates 4 domain scores and a total score, the mean of the 4 domain scores. Identical scoring for each of the four MENQOL domains is used. A 0 is identical that the woman has not experienced this specific symptom in the previous month; Score 1 demonstrates that the woman experienced the symptom, but it did not bother her; Scores 2 through 7 demonstrate an increasing level of the bothering symptom, so that these scores indicate increasing levels of bother experienced from the symptom and correspond to the ''1'' through ''6'' checkboxes on the MENQOL. With increasing MENQOL scores, levels of bother experienced from the symptom are increased as well. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Сhanges in the level of sex hormones after using higher doses estrogen therapy | Assessment of changes in the level of sex hormone in peripheral blood: estradiol (pmol/l). Reference values: 150 - 450 pmol/l. Blood sampling is performed at baseline and after 3 months. | 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. | 
| Сhanges in the level of sex hormones after using higher doses estrogen therapy | Assessment of changes in the level of sex hormone in peripheral blood: total testosterone (nmol/l). Reference values: 0,52 - 2,5 nmol/l. Blood sampling is performed at baseline and after 3 months. | 3 months | 
| Сhanges in the level of FSH after using higher doses estrogen therapy |  | 3 months | 
| Сhanges in the level of E1 after using higher doses estrogen therapy |  | 3 months | 
| Сhanges in the level of E1S after using higher doses estrogen therapy |  | 3 months | 
| Сhanges in the level of SHBG after using higher doses estrogen therapy |  | 3 months | 
| Bone mineral density (BMD) response to using higher doses estrogen therapy for 12 Months |  | 12 Months |