Estetrol for the Treatment of Female Sexual Arousal Disorder in Postmenopausal Women

A Phase 2, Randomized, Double-blind, Placebo-controlled Proof-of-Concept Study to Evaluate the Efficacy and Safety of Estetrol in Postmenopausal Subjects With Female Sexual Arousal Disorder

This randomized, double-blind, placebo-controlled clinical trial investigated the effect of once daily oral administration of 20 mg estetrol monohydrate tablet for 12 weeks in postmenopausal women who experienced sexual arousal disorder. Specifically, the main aim was to evaluate whether estetrol (E4) is effective in the treatment of female sexual arousal disorder (FSAD) in women after their menopause.

Study Overview

• Status: Completed
• Conditions: Sexual Dysfunction, Physiological
• Intervention / Treatment: Other: Placebo; Drug: Estetrol

Detailed Description

Female Sexual Arousal Disorder (FSAD), a subtype of female sexual dysfunction, is an inability to attain or to maintain an adequate lubrication-swelling response of sexual excitement. FSAD may manifest as a decrease in vaginal lubrication and a decrease in genital sensation related to blood flow and can cause marked distress and/or interpersonal difficulty (Diagnostic and Statistical Manual (DSM) of Mental Disorders, 4th edition [DSMIV]). Estrogen has a role in maintaining genital tissue structural integrity and pelvic nerve-stimulated genital blood flow.

This study was conducted with estetrol (E4), assessing the efficacy and safety of estetrol monohydrate 20 mg (E4 20 mg), equivalent to estetrol 18.9 mg, for the treatment of FSAD associated with menopause in hysterectomized postmenopausal women.

The design of this Phase 2, Proof of Concept (POC) study was: randomized, double-blind, placebo-controlled, two-arm parallel group. Eligible subjects were randomized in a 1:1 ratio and received either an oral tablet of E4 20 mg or placebo, once daily for 12 weeks. Placebo tablet looked identical to E4 but had no active ingredient. During the study, participants visited the clinic 7 times and completed a daily e-diary. The results were evaluated regarding the effect of E4 and placebo on the sexual arousal of the participants, using several validated questionnaires.

The primary efficacy endpoints were the change from Baseline to Week 12:

• in feeling concerned by difficulties with sexual arousal, assessed by Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) Item 14;
• in the Sexual Function Questionnaire (SFQ-28) Arousal-Sensation Domain (Questions 6 to 9).

Secondary efficacy endpoints were the change from Baseline to Week 12:

• in arousal and lubrication assessed by Patient-Reported Outcomes Measurement Information System-Sexual Function and Satisfaction (PROMIS-SexFS) Questionnaire;
• in sexual function assessed by FSDS-DAO - total score and by percentage of Satisfying Sexual Event (SSE) captured in e-diary;
• in sexual function assessed by SFQ-28 - total score;
• in sexual function assessed by PROMIS-SexFS;
• in severity of sexual arousal disorder as assessed by Patient Global Impression of Severity (PGIS).

The secondary efficacy endpoint Patient Global Impression of Change (PGIC) was assessed at Week 12.

• Study Type: Interventional
• Enrollment (Actual): 82
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Mesa, Arizona, United States, 85209
      • Estetra Study Site
    • Phoenix, Arizona, United States, 85032
      • Estetra Study Site
    • Tucson, Arizona, United States, 85715
      • Estetra Study Site
  • California
    • Pomona, California, United States, 91767
      • Estetra Study Site
    • San Diego, California, United States, 92111
      • Estetra Study Site
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Estetra Study Site
    • Miami, Florida, United States, 33173
      • Estetra Study Site
    • New Port Richey, Florida, United States, 34562
      • Estetra Study Site
    • Ocoee, Florida, United States, 34761
      • Estetra Study Site
    • Orlando, Florida, United States, 32801
      • Estetra Study Site
    • West Palm Beach, Florida, United States, 33409
      • Estetra Study Site
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Estetra Study Site
  • Illinois
    • Chicago, Illinois, United States, 60643
      • Estetra Study Site
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Estetra Study Site
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Estetra Study Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Estetra Study Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Estetra Study Site
    • Englewood, Ohio, United States, 45322
      • Estetra Study Site
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Estetra Study Site
  • Texas
    • Houston, Texas, United States, 77061
      • Estetra Study Site
    • Houston, Texas, United States, 77074
      • Estetra Study Site
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Estetra Study Site
  • Virginia
    • Virginia Beach, Virginia, United States, 23456
      • Estetra Study Site
  • Washington
    • Seattle, Washington, United States, 98104
      • Estetra Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria:

• Hysterectomized postmenopausal women, ≥40 up to ≤65 years, diagnosed with Female Sexual Arousal Disorder

Main Exclusion Criteria:

• Not willing to stop any hormonal products during their participation in the study
• History of unresolved sexual trauma or abuse that is contributing to any sexual dysfunction problem
• Have experienced a recent major life stress or relationship discord that could interfere with sexual activity
• Clinically significant abnormal gynecological findings
• History of malignancy, with the exception of basal cell or squamous cell carcinoma of the skin
• Systolic BP higher than 140 mmHg, diastolic BP higher than 90 mmHg
• Is judged by the investigator to be unsuitable for any reason

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Estetrol; Estetrol monohydrate 20 mg, administered orally once daily for up to 12 weeks	Drug: Estetrol; Estetrol monohydrate 20 mg, equivalent to estetrol 18.9 mg; Other Names: E4
Placebo Comparator: Placebo; Matching Placebo, administered orally once daily for up to 12 weeks	Other: Placebo; Matching Placebo to E4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 12 in Feeling Concerned by Difficulties With Sexual Arousal, Assessed by Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO), Item 14	The Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) is a validated 15-item self-assessment where each item is scored from 0 (never) to 4 (always). Higher scores on this scale, which has a total range of 0-60, indicate greater distress. Item 14 assesses how often the subject has felt concerned by difficulties with sexual arousal during the past 30 days.	Baseline, Week 12.
Change From Baseline to Week 12 in the Sexual Function Questionnaire 28 (SFQ-28) Arousal-Sensation Domain (Questions 6 to 9)	The 28-item Sexual Function Questionnaire (SFQ-28) is a validated self-assessment tool to assess female sexual function. It has 8 domains, including domains for desire, arousal (sensation/lubrication/cognitive), orgasm, pain, enjoyment, and partner relationship. Questions are scored on a Likert scale (e.g., 0 to 5 or 1 to 5), where lower scores indicate higher levels of dysfunction. Questions 6, 7, 8, and 9 deal with the domain "Arousal-sensation". Score range for this domain is: 4-20 (=sum of Questions 6-9). Total score range is: 24-141 (=sum of all Questions 1-28).	Baseline, Week 12.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 12 in Arousal and Lubrication Assessed by Patient Reported Outcomes Measurement Information System (PROMIS) Sexual Function and Satisfaction (SexFS) Measures (PROMIS-SexFS Questionnaire)	The PROMIS-SexFS is an instrument to measure self-reported sexual function and satisfaction. In total, 24 questions (out of 26) are rated on a 5-point scale each, so that for each question, the score range may be 1-5 or 0-5 (0=not applicable). Questions (Q) can be grouped by domains; their scores are summed to calculate the domain score. There are 11 domains in total. A higher score indicates a better outcome in the following domains: arousal and lubrication (3Q; 3-15), interest in sexual activity (2Q, score range: 2-10), orgasm-pleasure (2Q; 0-10), orgasm-ability (1Q; 0-5), and satisfaction with sex life (4Q; 3-20). A higher score indicates a worse outcome in the following domains: vaginal discomfort (2Q; 2-10), vulvar discomfort (2Q; 2-10), vulvar dysfunction (2Q; 2-10), oral discomfort (2Q; 2-10), oral dryness (2Q; 2-10), anal discomfort (2Q; 2-10). The 2 remaining questions of the questionnaire are for screening purposes.	Baseline, Week 12.
Change From Baseline to Week 12 in Sexual Function Assessed by FSDS-DAO -- Total Score	The Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) is a validated 15-item self-assessment where each item is scored from 0 (never) to 4 (always). Higher scores on this scale, which has a total range of 0-60, indicate greater distress.	Baseline, Week 12.
Change From Baseline to Week 12 in Sexual Function Assessed by Percentage of Satisfying Sexual Events (SSE) -- Captured in Arousal Electronic Diary (Ediary)	A higher number of Satisfying Sexual Events (SSE) indicates an improvement in sexual function. The arousal electronic diary contains a questionnaire to be completed by the subject within 24 hours of a sexual event.	Baseline, Week 12.
Change From Baseline to Week 12 in Sexual Function Assessed by the Sexual Function Questionnaire 28 (SFQ-28) -- Total Score	The 28-item Sexual Function Questionnaire (SFQ-28) is a validated self-assessment tool to assess female sexual function. It has 8 domains, including domains for desire, arousal (sensation/lubrication/cognitive), orgasm, pain, enjoyment, and partner relationship. Questions are scored on a Likert scale (e.g., 0 to 5 or 1 to 5), where lower scores indicate higher levels of dysfunction. Questions 6, 7, 8, and 9 deal with the domain "Arousal-sensation". Score range for this domain is: 4-20 (=sum of Questions 6-9). Total score range is: 24-141 (=sum of all Questions 1-28).	Baseline, Week 12.
Change From Baseline to Week 12 in Sexual Function Assessed by PROMIS-SexFS	Refer to Description of Outcome Measure #3.	Baseline, Week 12.
Patient Global Impression of Change (PGIC) at Week 12	Patient Global Impression of Change (PGIC) was used to measure changes in sexual arousal disorder. At Week 12, each enrolled subject was asked to rate their change in sexual arousal on 7-point Likert scale. The results are presented as the number of participants. The grading of responses were from 'No Change' to 'A Great Deal Better', as shown in the results table below.	Week 12.
Change From Baseline to Week 12 in Severity of Sexual Arousal Disorder as Assessed by Patient Global Impression of Severity (PGIS)	Patient Global Impression of Severity (PGIS) was used to evaluate the severity of sexual arousal disorder at a given time. The subject is asked to rate the severity of their sexual arousal dysfunction on 7-point Likert scale (1=not present, 2=very mild, 3=mild, 4=moderate, 5=moderately severe, 6=severe, and 7=extremely severe). A lower score indicates an improvement.	Baseline, Week 12.

Other Outcome Measures

Outcome Measure	Time Frame
Frequency of treatment emergent adverse events (TEAEs) (including treatment-emergent serious adverse events [TESAEs]).	12 weeks
Blood pressure (systolic and diastolic) at each measured time point.	12 weeks
Respiratory rate at each measured time point.	12 weeks
Heart rate at each measured time point.	12 weeks

Collaborators and Investigators

• Sponsor: Estetra

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2024
• Primary Completion (Actual): March 14, 2025
• Study Completion (Actual): April 21, 2025

Study Registration Dates

• First Submitted: January 23, 2024
• First Submitted That Met QC Criteria: March 12, 2024
• First Posted (Actual): March 13, 2024

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Female Sexual Arousal Disorder; FSAD
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Sexual Dysfunction, Physiological; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Estriol; Estetrol
• Other Study ID Numbers: MIT-Do001-C206

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No