Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I)

Mean change from Baseline to Week 1 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 1 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 1. Mean change = mean weekly frequency at Week 1 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 1 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 1. Baseline and Week 1 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 1 - mean severity score at Baseline

Time frame: Baseline and Week 1

Mean change from Baseline to Week 2 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 2 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 2. Mean change = mean weekly frequency at Week 2 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 2 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 2. Baseline and Week 2 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 2 - mean severity score at Baseline

Time frame: Baseline and Week 2

Mean change from Baseline to Week 3 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) ((Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 3 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 3. Mean change = mean weekly frequency at Week 3 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 3 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 3. Baseline and Week 3 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 3 - mean severity score at Baseline

Time frame: Baseline and Week 3

Mean change from Baseline to Week 4 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy part)

The weekly frequency of moderate to severe VMS at Baseline and Week 4 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 4. Mean change = mean weekly frequency at Week 4 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 4 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 4. Baseline and Week 4 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 4 - mean severity score at Baseline

Time frame: Baseline and Week 4

Mean change from Baseline to Week 5 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 5 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 5. Mean change = mean weekly frequency at Week 5 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 5 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 5. Baseline and Week 5 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 5 - mean severity score at Baseline

Time frame: Baseline and Week 5

Mean change from Baseline to Week 6 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 6 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 6. Mean change = mean weekly frequency at Week 6 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 6 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 6. Baseline and Week 6 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 6 - mean severity score at Baseline

Time frame: Baseline and Week 6

Mean change from Baseline to Week 7 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 7 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 7. Mean change = mean weekly frequency at Week 7 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 7 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 7. Baseline and Week 7 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 7 - mean severity score at Baseline

Time frame: Baseline and Week 7

Mean change from Baseline to Week 8 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 8 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 8. Mean change = mean weekly frequency at Week 8 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 8 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 8. Baseline and Week 8 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 8 - mean severity score at Baseline

Time frame: Baseline and Week 8

Mean change from Baseline to Week 9 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 9 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 9. Mean change = mean weekly frequency at Week 9 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 9 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 9. Baseline and Week 9 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 9 - mean severity score at Baseline

Time frame: Baseline and Week 9

Mean change from Baseline to Week 10 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 10 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 10. Mean change = mean weekly frequency at Week 10 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 10 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 10. Baseline and Week 10 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 10 - mean severity score at Baseline

Time frame: Baseline and Week 10

Mean change from Baseline to Week 11 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 11 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 11. Mean change = mean weekly frequency at Week 11 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 11 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 11. Baseline and Week 11 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 11 - mean severity score at Baseline

Time frame: Baseline and Week 11

Mean change from Baseline to Week 12 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week 12 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 12. Mean change = mean weekly frequency at Week 12 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 12 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 12. Baseline and Week 12 severity score = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 12 - mean severity score at Baseline

Time frame: Baseline and Week 12

Mean change from Baseline to Week 1 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 1 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 1. Baseline and Week 1 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 1 - mean severity score at Baseline

Time frame: Baseline and Week 1

Mean change from Baseline to Week 2 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 2 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 2. Baseline and Week 2 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 2 - mean severity score at Baseline

Time frame: Baseline and Week 2

Mean change from Baseline to Week 3 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 3 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 3. Baseline and Week 3 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 3 - mean severity score at Baseline

Time frame: Baseline and Week 3

Mean change from Baseline to Week 4 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 4 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 4. Baseline and Week 4 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 4 - mean severity score at Baseline

Time frame: Baseline and Week 4

Mean change from Baseline to Week 5 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 5 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 5. Baseline and Week 5 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 5 - mean severity score at Baseline

Time frame: Baseline and Week 5

Mean change from Baseline to Week 6 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 6 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 6. Baseline and Week 6 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 6 - mean severity score at Baseline

Time frame: Baseline and Week 6

Mean change from Baseline to Week 7 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 7 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 7. Baseline and Week 7 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 7 - mean severity score at Baseline

Time frame: Baseline and Week 7

Mean change from Baseline to Week 8 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 8 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 8. Baseline and Week 8 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 8 - mean severity score at Baseline

Time frame: Baseline and Week 8

Mean change from Baseline to Week 9 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 9 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 9. Baseline and Week 9 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 9 - mean severity score at Baseline

Time frame: Baseline and Week 9

Mean change from Baseline to Week 10 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 10 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 10. Baseline and Week 10 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 10 - mean severity score at Baseline

Time frame: Baseline and Week 10

Mean change from Baseline to Week 11 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 11 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 11. Baseline and Week 11 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 11 - mean severity score at Baseline

Time frame: Baseline and Week 11

Mean change from Baseline to Week 12 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part)

The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 12 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 12. Baseline and Week 12 severity score = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 12 - mean severity score at Baseline

Time frame: Baseline and Week 12

Percentage of participants with 50% reduction from Baseline in the weekly frequency of moderate to severe vasomotor symptoms (VMS) at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and day \[(X-1)\*7+1\] to day X\*7 (Week X).

Time frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

Percentage of participants with 50% reduction from Baseline in the weekly frequency of mild, moderate, and severe vasomotor symptoms (VMS) at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and day \[(X-1)\*7+1\] to day X\*7 (Week X).

Time frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

Percentage of participants with 75% reduction from Baseline in the weekly frequency of moderate to severe VMS at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and day \[(X-1)\*7+1\] to day X\*7 (Week X).

Time frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

Percentage of participants with 75% reduction from Baseline in the weekly frequency of mild, moderate, and severe VMS at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy Study Part)

The weekly frequency of moderate to severe VMS at Baseline and Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and day \[(X-1)\*7+1\] to day X\*7 (Week X).

Time frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

Percentage of participants with a clinically important difference (CID) compared to Baseline in the weekly frequency of moderate to severe VMS at Week 4 using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part)

The CGI score is a seven point scale in which subjects will be asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse.

Time frame: Week 4

Percentage of participants with a clinically important difference (CID) compared to baseline in the weekly frequency of moderate to severe VMS at Week 12 using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part)

The CGI score is a seven point scale in which subjects will be asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse.

Time frame: Week 12

Change from Baseline to Week 12 in vulvovaginal atrophy (VVA) symptoms (Efficacy Study Part)

Genitourinary syndrome of menopause (GSM) will be assessed by the subjects using the vulvovaginal atrophy (VVA) self assessment questionnaire. The following GSM symptoms will be assessed: * Vaginal dryness * Vaginal and/or vulvar irritation/itching * Dysuria * Vaginal pain associated with sexual activity * Vaginal bleeding associated with sexual activity All GSM symptoms except vaginal bleeding associated with sexual activity will be graded by the participants using the following scale: \[0\] none, \[1\] mild, \[2\] moderate, or \[3\] severe. Vaginal bleeding associated with sexual activity is documented using 2 categories: \[0\] absent or \[1\] present. A negative change from baseline score indicates improvement in symptoms.

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in the vulvovaginal atrophy (VVA) symptom that is initially identified by the participant as being the most bothersome using the VVA questionnaire at baseline (Efficacy Study Part)

Genitourinary syndrome of menopause (GSM) will be assessed by the subjects using the vulvovaginal atrophy (VVA) self assessment questionnaire. The following GSM symptoms will be assessed: * Vaginal dryness * Vaginal and/or vulvar irritation/itching * Dysuria * Vaginal pain associated with sexual activity * Vaginal bleeding associated with sexual activity All GSM symptoms except vaginal bleeding associated with sexual activity were graded by the participants using the following scale: \[0\] none, \[1\] mild, \[2\] moderate, or \[3\] severe. Vaginal bleeding associated with sexual activity was documented using 2 categories: \[0\] absent or \[1\] present. A negative change from baseline score indicates improvement in symptoms. At baseline the participant will be asked which of the above mentioned symptoms she identifies as being the most bothersome.

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in plasma concentration of triglycerides (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in plasma concentration of total cholesterol (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in the HDL-cholesterol ratio (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in plasma concentration of lipoprotein (a) (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in fasting glycaemia (Efficacy Study part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in plasma concentration of insulin (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in plasma concentration of glycated hemoglobin (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from Baseline to Week 12 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Efficacy Study Part)

Time frame: Baseline and Week 12

Change from baseline to Week 12 in health-related quality of life assessment (HRQoL) using the menopause-specific Quality of Life (MENQOL) questionnaire (Efficacy Study Part)

The MENQOL is self-administered questionnaire which will assess changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores will be converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

Time frame: Baseline and Week 12

Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part)

The CGI score is a seven point scale in which subjects will be asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse.

Time frame: Weeks 4 and 12

Number of participants with treatment-emergent adverse events (TEAEs) (Efficacy Study Part)

TEAEs are those adverse events occurring from time point of first ingestion of investigational product until last visit or any event already present that worsens in either intensity or frequency following exposure to the treatment.

Time frame: From baseline to Follow-up visit (up to Week 16)

Number of participants with changes in physical and gynecological examination results (Efficacy Study Part)

Physical examination will include an examination of general appearance, head, eyes, ears, nose, throat, skin, neck, lungs, breast, lymph nodes, abdomen, and the cardiovascular musculoskeletal and neurological systems. Gynecological examination will include a manual pelvic examination.

Time frame: Screening and Week 13

Number of participants with changes in vital sign results (Efficacy Study Part)

Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate.

Time frame: From screening to Week 13

Number of participants with changes in electrocardiogram (ECG) results (Efficacy Study Part)

The ECG interpretation scheme will include the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT and corrected QT (QTc) intervals, T waves, U waves and the presence or absence of any pathological changes.

Time frame: Screening and Week 13

Number of participants with changes in breast examination results (Efficacy Study Part)

Time frame: Screening and Week 13

Number of participants with changes in routine clinical laboratory test results (Efficacy Study Part)

Routine laboratory tests include hematology and chemistry.

Time frame: Screening, Baseline and Week 13

Change from baseline to each measured time point in endometrial thickness (Efficacy Study Part)

Endometrial thickness will be assessed by transvaginal ultrasound (TVUS). Baseline: data will be recorded at Screening.

Time frame: Screening, Week 13, Week 16

Frequency of subjects in the different endometrial categories according to Blaustein's pathology (Efficacy Study Part)

Endometrial biopsies will be centrally evaluated by three independent expert pathologists from different institutions, blinded to treatment group and to each other's readings. The concurrence of two of the three pathologists will be accepted as the final diagnosis. If there is no agreement among the three pathologists, the most severe pathologic diagnosis, i.e., atypical hyperplasia \>complex hyperplasia \>simple hyperplasia \>benign endometrium, will be used as the final diagnosis.

Time frame: Screening and Week 13

Number of participants with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Efficacy Study Part)

Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/ spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

Time frame: From Baseline up to Follow-up (Week 16)

Number of days with bleeding and/or spotting during each 28-day cycle of treatment (Efficacy Study Part)

Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

Time frame: From Baseline up to Follow-up (Week 16)

Number of participants with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Efficacy Study Part)

Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/ spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

Time frame: From Baseline up to Follow-up (Week 16)

Cumulative rates of amenorrhea (Efficacy Study Part)

The rate of amenorrhea is defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time.

Time frame: From Baseline up to Follow-up (Week 16)

Number of participants with treatment-emergent adverse events (TEAEs) (Endometrial and General Safety Part)

TEAEs are those adverse events occurring from time point of first ingestion of investigational product until last visit or any event already present that worsens in either intensity or frequency following exposure to the treatment.

Time frame: From baseline to Week 53

Number of participants with changes in physical and gynecological examination results (Endometrial and General Safety Part)

Physical examination will include an examination of general appearance, head, eyes, ears, nose, throat, skin, neck, lungs, breast, lymph nodes, abdomen, and the cardiovascular musculoskeletal and neurological systems. Gynecological examination will include a manual pelvic examination.

Time frame: Screening and Week 53

Number of participants with changes in vital sign results (Endometrial and General Safety Part)

Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate.

Time frame: From screening to Week 53

Number of participants with changes in breast examination results (Endometrial and General Safety Part)

Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate.

Time frame: From screening to Week 53

Number of participants with changes in electrocardiogram (ECG) results (Endometrial and General Safety Part)

The ECG interpretation scheme will include the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT and corrected QT (QTc) intervals, T waves, U waves and the presence or absence of any pathological changes.

Time frame: Screening and Week 53

Number of participants with changes in mammography results (Endometrial and General Safety Part)

Time frame: Screening and Week 53

Number of participants with changes in routine clinical laboratory test results (Endometrial and General Safety Part)

Routine laboratory tests include hematology and chemistry.

Time frame: Screening, Baseline and Week 13

Number of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Endometrial and General Safety Part)

Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

Time frame: From Baseline to Week 53

Number of days with bleeding and/or spotting during each 28-day cycle of treatment (Endometrial and General Safety Part)

Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

Time frame: From Baseline to Week 53

Number of participants with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Endometrial and General Safety Part)

Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

Time frame: From Baseline to Week 53

Cumulative rates of amenorrhea (Endometrial and General Safety Part)

The rate of amenorrhea is defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time.

Time frame: From Baseline to Week 53

Change from Baseline to Weeks 12 and 52 in health-related quality of life assessment (HRQoL) using the menopause-specific Quality of Life (MENQOL) questionnaire (Endometrial and General Safety Part)

The MENQOL is self-administered questionnaire which will assess changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

Time frame: Baseline and Weeks 12 and 52

Total score in treatment satisfaction assessed after 4, 12 and 52 weeks of treatment using the Clinical Global Impression (CGI) questionnaire (Endometrial and General Safety Part)

The CGI score is a seven point scale in which subjects will be asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse.

Time frame: Weeks 4, 12, and 52

Change from Baseline to Weeks 12 and 52 in plasma concentration of triglycerides (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in plasma concentration of high-density lipoprotein (HDL)-cholesterol (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in plasma concentration of total cholesterol (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in plasma concentration of lipoprotein (a) (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in fasting glycaemia (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in plasma concentration of insulin (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in plasma concentration of glycated hemoglobin (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to Weeks 12 and 52 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Endometrial and General Safety Part)

Time frame: Baseline and Weeks 12 and 52

Change from Baseline to each measured time point in endometrial thickness (Endometrial and General Safety Study Part)

Endometrial thickness will be assessed by transvaginal ultrasound (TVUS).

Time frame: Screening, Baseline, Weeks 13, 29, and 53

Frequency of subjects in the different endometrial categories according to Blaustein's pathology (Endometrial and General Safety Study Part)

Endometrial biopsies will be centrally evaluated by three independent expert pathologists from different institutions, blinded to treatment group and to each other's readings. The concurrence of two of the three pathologists will be accepted as the final diagnosis. If there is no agreement among the three pathologists, the most severe pathologic diagnosis, i.e., atypical hyperplasia \>complex hyperplasia \>simple hyperplasia \>benign endometrium, will be used as the final diagnosis.

Time frame: Screening and Week 53