Mirena and Estrogen for Control of Perimenopause Symptoms and Ovulation Suppression

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01613131
• Collaborator: Bayer (Industry)
• Enrollment: 39
• Location: 1
• Arms: 2
• Duration (Months): 26
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

Hormonal treatment of perimenopausal women has frequently utilized oral contraceptive pills (OCPs). Because of their ability to suppress ovulation and establish cycle control, OCPs have become a popular option, and one that is FDA approved for use until menopause. However, use of OCPs in women in their 40's and 50's carries significant cardiovascular risks. Venous thromboembolism risk is 3-6 fold greater in OCP users, and the risk of myocardial infarction (MI) is approximately doubled in OCP users over the age of 40. This occurs at an age where the background population risk of MI begins to increase, such that the absolute number of cases rises substantially. Women with additional risk factors for cardiovascular disease have a much greater risk for MI (6-40-fold) in association with OCPs. There are also large subgroups of midlife women who are not candidates for OCP use, such a smokers and migraineurs. Moreover, the trend towards lower estrogen dosing with OCPs containing 20 micrograms of ethinyl estradiol has not led to a detectable decrease in thromboembolic risk.

Because of their increased potential risks, it is appropriate to seek alternatives to OCPs and to explore lower doses of hormones to relieve perimenopausal symptoms that occur prior to a woman's final menses. Recent evidence indicates that the hypothalamic-pituitary axis of reproductively aging women is more susceptible to suppression by sex steroids that previously believed. It is possible that hormone doses as low as 50 micrograms of transdermal estradiol (TDE) can suppress the hypothalamic-pituitary axis of midlife women. It is also tempting to speculate that the low but measurable circulating doses of levonorgestrel that are present when a woman uses the Mirena intrauterine system (IUS) can contribute to or even independently suppress the hypothalamic-pituitary axis, and reduce the hormonal fluctuations that result in worsening of perimenopausal symptoms. The combination of low dose TDE plus Mirena may therefore confer superior symptom control as well as contraceptive effectiveness, at far less risk.

Condition or Disease	Intervention/Treatment	Phase
Menopausal and Other Perimenopausal Disorders	Drug: Mirena; Drug: Estradiol; Drug: Placebo Gel	N/A

Detailed Description

The Specific Aims of the present proposal are therefore as follows:

Aim 1: To test the hypothesis that low dose estrogen therapy in concert with the low doses of levonorgestrel that circulate when Mirena is used will suppress ovulation in perimenopausal women.

Aim 2: To examine ovulation rates and symptom control with Mirena alone, and to assess the tolerability of combined estrogen therapy plus the Mirena IUS as a treatment option for symptomatic perimenopausal women.

The proposed pilot study is designed to test the feasibility and tolerability of the proposed regimens: Mirena alone or Mirena plus low-dose TDE in treating symptoms in perimenopausal women and to provide the preliminary data for a larger, comparative effectiveness study of optimal symptom control and provision of long term contraception for midlife women within 5 years of their final menstrual period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effectiveness of Perimenopausal Hormone Therapy in Suppression of Ovulation, Stabilization of Reproductive Hormones and Symptom Control
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Mirena + Estradiol Gel Subjects will be assigned to use of Estradiol gel for use with Mirena.	Drug: Mirena; Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months).; Other Names: IUD ; Drug: Estradiol; Topical, .06%, Applied once daily for 50 days.; Other Names: TDE
Placebo Comparator: Mirena + Placebo Gel Subjects will be assigned to use of placebo gel for use with Mirena.	Drug: Mirena; Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months).; Other Names: IUD ; Drug: Placebo Gel; Topical Gel, Applied once daily for 50 days, Placebo comparator.; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. Hot Flashes [Day 0]

   The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.

2. Sleep [Day 0]

   The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.

3. Depression [Day 0]

   The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.

4. Fatigue [Day 0]

   The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.

5. Sleep [Day 90]

   The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.

6. Sleep [Day 140]

   The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.

7. Hot Flashes [Day 90]

   The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.

8. Hot Flashes [Day 140]

   The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.

9. Depression [Day 90]

   The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.

10. Depression [Day 140]

    The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.

11. Fatigue [Day 90]

    The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.

12. Fatigue [Day 140]

    The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 52 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 40-52

• History of regular menstrual cycles every 20-35 days in mid-reproductive life (20-35 years of age)

• At least 1 period within the past 3 months

• BMI less than 35 kg/m2

• Presence of at least one of the following perimenopausal symptoms:

1. Hot flashes (vasomotor symptoms)

2. Cyclical headache, bloating or adverse mood

3. Self-reported poor quality of sleep

Exclusion Criteria:

• Age < 40 years

• Hysterectomy or bilateral oophorectomy

• Cigarette smoking

• Signs or symptoms of restless leg syndrome or sleep apnea

• Any chronic renal or hepatic disease that might interfere with excretion of gonadotropins or sex steroids

• Moderate/vigorous aerobic exercise > 4 hours per week

• Inability to read/write English

• Pregnant Women

• Prisoners

• Decisionally challenged subjects

• Any medical condition that makes use of Topical estradiol or Mirena contraindicated.

• Sex hormone use within the past 30 days

• History of cancer, blood clots or blood clotting disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• Bayer

Investigators

• Principal Investigator: Nanette Santoro, MD, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01613131
• Other Study ID Numbers: 11-1711
• First Posted: Jun 6, 2012
• Last Update Posted: Dec 2, 2015
• Last Verified: Oct 1, 2015

• Additional relevant MeSH terms: Estradiol

Study Results

Participant Flow

Recruitment Details	Women were recruited from the University of Colorado Denver campus by direct physician referral or from advertisements in the University community.
Pre-assignment Detail	Women using systemic hormonal contraception (patch, pill, ring) were required to have a 30 day hormone washout prior to placement. One subject signed the consent, but failed to meet the inclusion/exclusion criteria during the screening process. Thus, there were 39 women that were enrolled, but only 38 that started in the participant flow.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Period Title: Overall Study
STARTED	20	18
COMPLETED	17	13
NOT COMPLETED	3	5

Baseline Characteristics

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel	Total
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.	Total of all reporting groups
Overall Participants	20	18	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	18 100%	38 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	20 100%	18 100%	38 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%	18 100%	38 100%

Outcome Measures

1. Primary Outcome

Title	Hot Flashes
Description	The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	20	18
Mean (Standard Error) [scores on a scale]	10.3 (2.653)	7.944 (2.85)

2. Primary Outcome

Title	Sleep
Description	The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	20	18
Mean (Standard Error) [scores on a scale]	9.80 (1.13)	8.83 (1.01)

3. Primary Outcome

Title	Depression
Description	The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

Two women in the Mirena + Placebo Gel did not provide complete data for this outcome measure; thus they were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	20	16
Mean (Standard Error) [scores on a scale]	9.8 (1.34)	11.31 (2.27)

4. Primary Outcome

Title	Fatigue
Description	The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

One woman in the Mirena + Placebo Gel arm did not provide complete data for this outcome measure; thus she was not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	20	17
Mean (Standard Error) [scores on a scale]	3.38 (.32)	3.90 (.34)

5. Primary Outcome

Title	Sleep
Description	The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

3 women in the Mirena + Estradiol Gel arm, and 5 women in the Mirena + Placebo Gel did not provide complete data; thus, were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	17	13
Mean (Standard Error) [scores on a scale]	9.24 (1.04)	9.31 (1.37)

6. Primary Outcome

Title	Sleep
Description	The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.
Time Frame	Day 140

Outcome Measure Data

Analysis Population Description

5 women in the Mirena + Estradiol Gel arm, and 7 women in the Mirena + Placebo Gel did not provide complete data; thus, were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	15	11
Mean (Standard Error) [scores on a scale]	8.67 (1.10)	7.46 (1.46)

7. Primary Outcome

Title	Hot Flashes
Description	The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

3 women in the Mirena + Estradiol Gel arm, and 5 women in the Mirena + Placebo Gel did not provide complete data; thus, were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	17	13
Mean (Standard Error) [scores on a scale]	12.71 (3.70)	5.31 (2.62)

8. Primary Outcome

Title	Hot Flashes
Description	The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.
Time Frame	Day 140

Outcome Measure Data

Analysis Population Description

3 women in the Mirena + Estradiol Gel arm, and 5 women in the Mirena + Placebo Gel did not provide data; thus, were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	17	13
Mean (Standard Error) [scores on a scale]	7.18 (2.12)	9.54 (4.09)

9. Primary Outcome

Title	Depression
Description	The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

4 women in the Mirena + Estradiol Gel arm, and 5 women in the Mirena + Placebo Gel did not provide complete data; thus, were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	16	13
Mean (Standard Error) [scores on a scale]	9.69 (1.46)	11.46 (2.92)

10. Primary Outcome

Title	Depression
Description	The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.
Time Frame	Day 140

Outcome Measure Data

Analysis Population Description

3 women in the Mirena + Estradiol Gel arm, and 6 women in the Mirena + Placebo Gel did not provide complete data; thus, were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	17	12
Mean (Standard Error) [scores on a scale]	11.41 (1.80)	12.08 (2.56)

11. Primary Outcome

Title	Fatigue
Description	The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

3 women in the Mirena + Estradiol Gel arm, and 6 women in the Mirena + Placebo Gel did not provide complete data; thus, were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	17	12
Mean (Standard Error) [scores on a scale]	3.54 (.34)	3.80 (.35)

12. Primary Outcome

Title	Fatigue
Description	The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.
Time Frame	Day 140

Outcome Measure Data

Analysis Population Description

3 women in the Mirena + Estradiol Gel arm, and 5 women in the Mirena + Placebo Gel did not provide complete data; thus, were not included in the analysis for this timepoint.

Arm/Group Title	Mirena + Estradiol Gel	Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.	Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
Measure Participants	17	13
Mean (Standard Error) [scores on a scale]	2.78 (.27)	3.90 (.39)

Adverse Events

Time Frame	140 days
Arm/Group Title	Mirena + Estradiol Gel		Mirena + Placebo Gel
Arm/Group Description	Subjects will be assigned to use of Estradiol gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Estradiol: Topical, .06%, Applied once daily for 50 days.		Subjects will be assigned to use of placebo gel for use with Mirena. Mirena: Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months). Placebo Gel: Topical Gel, Applied once daily for 50 days, Placebo comparator.
All Cause Mortality
	Mirena + Estradiol Gel		Mirena + Placebo Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Mirena + Estradiol Gel		Mirena + Placebo Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Mirena + Estradiol Gel		Mirena + Placebo Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		1/18 (5.6%)
General disorders
Mood changes	1/20 (5%)	1	1/18 (5.6%)	1

Limitations/Caveats

The main limitation was the sample size, which is consistent with a pilot study, and which can only inform the design of future research.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.