Clinical trial NCT03116022: Use of Estriol at Distal Third of Vagina Improving Coital Pain in Post-menopause Women
Official title: Use of Estriol at Distal Third of the Vaginal Wall Relieving Coital Pain in Women After Menopause: a Randomized, Blinded and Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Dyspareunia
Menopause
Sexual Dysfunction
Keywords: menopause
sexual dysfunction
coital pain
vagina
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
First posted: 2017-04-14
Enrollment: 125
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: we compared three groups: women using estriol in the proximal vagina wall, women using estriol in the distal vagina wall, and women using gel lubricant
Primary purpose: TREATMENT

Brief summary: Hypoestrogenism leads to vaginal wall changes resulting in diminished vaginal lubrication and, consequently, causing pain during intercourse. Topical estrogen therapy (THT) may control this complaint. However, there are limitations on its use, especially in patients with breast cancer and diagnosed endometrial cancer. This randomized clinical trial aims to assess the impact of local estriol therapy in postmenopausal women complaining of coital pain and to assess serum concentrations of estriol in these women after estriol use. One-hundred-thirty-two women aged between 40 and 65 years will be randomized into three groups: Women using estriol 1 mg / 1g at the proximal third of vagina every other night - estriol proximal group (PEG), women in using estriol 1 mg / 1g at the distal third of the vagina every other night - estriol distal group (DEG), gel group (GG) using water-based during intercourse.

Detailed description: Introduction The daily application of estrogen in the vagina can improve the hydrogen potential (pH), vaginal dryness, burning sensation, dyspareunia, and urinary symptoms. Dyspareunia is highly prevalent after menopause as well as in women after gynecological and breast cancer treatment. However, prescription of topical estrogen therapy (THT) to these women is still controversial, and they are allowed to use only moisturizing cream and vaginal lubricants.

Studies have shown increased serum concentrations of estrogens (estradiol and estrone) after intravaginal suppository containing estradiol use. However, a cohort of 13,479 women treated for breast cancer, 271 received topical hormone therapy (THT), and no increased risk for recurrence was shown in this population.

The main blood supplement to the vagina is mainly from vessels that irrigate proximal vaginal wall, a region where possibly the drug uptake is more intense. However, one study showed that the concentration of estradiol is similarly high regardless of whether the drug was applied to the proximal or distal wall of the vagina. Nevertheless, this study has not been replicated yet.

THT promotes an improvement of coital pain when used in the proximal vagina, but a large population of women with clinical conditions such as thrombophilia and breast cancer cannot benefit from this resource. It is not known if the estriol applied in the distal vagina wall can lead to high serum levels of this hormone.

OBJECTIVES This study aims to evaluate the impact of topic estriol therapy applied in distal vagina wall in coital pain, sexual function, and mood after estriol use. To evaluate serum level of this hormone after estriol use.

METHODS Study design This is a prospective, blind, and randomized clinical trial including post-menopausal women complaining of pain during intercourse. The selected women will be randomized into three groups: estriol proximal group (PEG), estriol distal group (DEG), and gel group (GG). Participants and the assistance staff will not be blinded to the intervention.

Sample Size The sample size was based on the estimated Cohen effect size. Assuming an effect size measure of 0.7 (considered large by Cohen) between groups, and considering a power test of 90% and a significance level of 5%, at least 44 subjects in each arm are required for a total of 132 participants.

Randomization Randomization will be conducted in blocks of random sizes to generate the random allocation sequence. Participants will be randomized in 23 blocks and distributed in intervention groups according to their position in each block.

Participants Sexually-active post-menopausal women between 40 to 65 years old complaining of coital pain will be invited to participate in this study. Sexual activity must include penis-vagina penetration.

Hormonal profile evaluation Blood samples will be collected before the intervention to measure basal serum levels of fasting glucose, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH) and serum estriol. These parameters will be applied in the 12th week of intervention. The measurements of FSH, TSH, and estriol will be performed by chemiluminescence with IMMULITE® 2000 device (DPC IMMULITE® 2000 (Diagnostic Products Corporation, Los Angeles, California, United States of America (USA)). For the measurement of estriol free will be used IMMULITE® kit 2000 unconjugated estriol (SIEMENS, USA). The measurement of hormonal status will be held before the intervention (time 1) and at the end of the intervention (12 weeks). Glucose will be determined by automated spectrophotometry using the liquid enzymatic glycemia kit (Wiener Laboratory, 2000, Rosario, Argentina) Sexual function Sexual function will be evaluated with the Female Sexual Function Index (FSFI). It has 19 questions, with 6 subscales that assess desire, arousal, lubrication, orgasm, satisfaction, and pain. Each question is multiple choice and scored from 0 or 1 to 5. For calculation of the total score (range: 2 to 36), the score of each subscale was multiplied by a factor, and the 6 scores were summed. A lower score corresponds to a worse sexual function, and a score below 26.55 indicates sexual dysfunction.

Emotional condition The Hospital Anxiety and Depression Scale (HAD) was used to assess mood. This scale has 14 items and two subscales, with 7 questions regarding anxiety (HAD-A) and 7 regarding depression (HAD-D). There are four responses to each question (score of 0 to 3), and the sum of scores of each subscale provides a total score from 0 to 21. A cut-off score ≥ 9 for anxiety and depression characterizes the mental state of the woman.

All questionnaires will be applied individually by a gynecologist before the intervention (time 1) and at the end of the intervention (12 weeks) when women attend to collect blood samples. Before applying the questionnaires, women will be informed about the content and objectives of the research, and will also be informed about the issue of confidentiality.

Coital pain evaluation Coital pain will be assessed by the Analogic Visual Scale and the McGill Pain Questionnaire, a multi-dimensional tool that consists of 4 groups of constructs divided into 20 subgroups: Sensory-discriminative group (subgroups 1 to 10) relates to traction, heat, twist, among others; the motivational-affective group (subgroups 11 to 15) describes the affective dimension aspects of tension, as well as fear punishment, and neurovegetative responses; the descriptors of the cognitive component evaluation (subgroup 16) allows the patient to express the overall assessment of the painful experience; subgroups 17-20 comprise miscellaneous items. The subject can choose only one alternative for each subgroup, so the greater the number of most marked pain intensity descriptors, wherein the maximum score is 78. This questionnaire will be applied individually by a gynecologist at the beginning and at 12 weeks of intervention.

INTERVENTION For the PEG group, women will receive professional guidance to use an applicator only 3 cm inside the vagina, once at night, each other night, while lying down to sleep, with a woman in the dorsal position inserting the applicator 3 cm through the vaginal introitus. For the DEG group, women will receive professional guidance to use an applicator totally inside the vagina. The application will be recommended once each other night, while lying down to sleep, with a woman in the dorsal position inserting the applicator 10 cm through the vaginal introitus. Lubricant will be acquired by the researcher in commercial form and should be used during sexual intercourse in the vagina introitus prior to penetration of the penis.

Certification of correct use of prescription A researcher will contact the patient by telephone every two weeks to certify the proper use or any adverse symptoms related to the use of medication.

ETHICAL ASPECTS This project was approved by the Institutional Ethics Committee in Research, and all women shall sign the Informed Consent. This project will be guided according to the ethical standards by Resolution 196/96 of the National Health Council on research with the human being.

Statistical analysis Qualitative variables are described considering the absolute and relative frequencies, as quantitative variables are expressed by central position and dispersion measurements. The comparison between the study groups will be performed using the linear regression model of mixed effects; the model residue analysis will be representing through normal graphics. Cohen measure will be used as the size measure, which is expressed by the difference between the mean divided by the standard deviation. The Statistical Analysis System (SAS) will be used for data analysis.

Eligibility criteria: Inclusion Criteria:

* Women with a clinical diagnosis of menopause
* FSH\> 40 milli-International unit (mIU/ml)
* Having sex including penetration of penis into vagina
* Pain during penetration
* Active sexual partners
* Stable relationship.

Exclusion Criteria:

* Previous use of steroids in genital area in the last month
* Thromboembolism history
* Renal insufficiency
* Cholestatic jaundice
* Degenerative vulvar pathology
* Breast cancer
* Endometrial cancer
* Vulvar cancer
* Vaginal cancer history
* Prior radiotherapy to the genital region
* Smoking
* Acute urogenital infections
* Vulvovaginitis
* Urinary tract infection
* Genital herpes
* Genital prolapse grades II, III and IV by Baden Walker
* Systemic hormonal therapy in the last three months
* Use of antidepressants drugs
* Diabetes
* Thyroid disorder
* Cognitive restrictions

Primary outcomes:
measure: Improvement in pain score after estriol use
timeFrame: baseline and 12 weeks
Secondary outcomes:
measure: Number of participants with risk for sexual dysfunction after estriol use
timeFrame: baseline and week 12
measure: Number of participants with risk for anxiety after estriol use
timeFrame: baseline and week 12
measure: Number of participants with risk for depression after estriol use
timeFrame: baseline and week 12
measure: Reduction of de degree of coital pain
timeFrame: baseline and week 12
measure: Variation in serum levels of estriol after estriol use
timeFrame: Assessment of serum concentration of estriol at baseline and week 12.
measure: Variation in serum levels of follicle-stimulating hormone after estriol use
timeFrame: Assessment of serum concentration of follicle-stimulating hormone at baseline and week 12.
measure: Variation in serum levels of thyroid-stimulating hormone after estriol use
timeFrame: Assessment of serum concentration of thyroid-stimulating hormone at baseline and week 12.
measure: Number of participants with adverse events that are related to estriol use
timeFrame: Assessment of laboratory values at baseline and week 12. Adverse events assessed each 4 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months.
measure: Variation in blood glucose after estriol use
timeFrame: Assessed at baseline and on week 12
measure: Variation in weight after estriol use Weight
timeFrame: Assessed at baseline and on week 12
measure: Variation in body mass index (BMI) after estriol use
timeFrame: Assessed at baseline and on week 12
Other outcomes:
Locations:
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas de Ribeirão Preto
state: SP
Study officials:
affiliation: Faculdade de Medicina de Ribeirão Preto - Universidade de Sao Paulo
name: lucia a Silva Lara, PhD
role: PRINCIPAL_INVESTIGATOR
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