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

Sponsor

Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT05737329

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Ovarian Insufficiency	Drug: Transdermal estradiol gel 0.1% 1.5mg/ day Drug: Transdermal estradiol gel 0.1% 2.0mg/ day	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

80 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

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.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 (Participant)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 1, 2019

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Other: Transdermal estradiol gel 0.1% 1.5mg/ day 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 Estradiol gel 0.1% 1.5mg/ daily + Micronized Progesterone 200mg Drug: Transdermal estradiol gel 0.1% 2.0mg/ day Estradiol gel 0.1% 2.0mg/ daily + Micronized Progesterone 200mg
Other: Transdermal estradiol gel 0.1% 2.0mg/ day 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 Estradiol gel 0.1% 1.5mg/ daily + Micronized Progesterone 200mg Drug: Transdermal estradiol gel 0.1% 2.0mg/ day Estradiol gel 0.1% 2.0mg/ daily + Micronized Progesterone 200mg

Arm

Intervention/Treatment

Other: Transdermal estradiol gel 0.1% 1.5mg/ day

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

Estradiol gel 0.1% 1.5mg/ daily + Micronized Progesterone 200mg

Drug: Transdermal estradiol gel 0.1% 2.0mg/ day

Estradiol gel 0.1% 2.0mg/ daily + Micronized Progesterone 200mg

Other: Transdermal estradiol gel 0.1% 2.0mg/ day

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

Estradiol gel 0.1% 1.5mg/ daily + Micronized Progesterone 200mg

Drug: Transdermal estradiol gel 0.1% 2.0mg/ day

Estradiol gel 0.1% 2.0mg/ daily + Micronized Progesterone 200mg

Outcome Measures

Primary Outcome Measures

Evaluation of the severity of estrogen deficiency symptoms [3 months]
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.
Changing the assessment of quality of life using the Short Form Health Survey-36 (SF-36) [3 months]
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.
Changing the assessment of menopause-related quality of life measured using the Menopause-Specific Quality of Life (MENQOL) questionnaire. [3 months]
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.

Secondary Outcome Measures

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: testosterone (nmol/l). Reference values: 0,52 - 2,5 nmol/l. Blood sampling is performed at baseline and after 3 months.]
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.
Сhanges in the level of sex hormones after using higher doses estrogen therapy [3 months]
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.
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare	Moscow		Russian Federation	117997

Sponsors and Collaborators

Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare

Investigators

Study Chair: Victoria Averkova, FSBI "National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov" Ministry of Healthcare of the Russian Federation