Sexual Dysfunction, Physiological
Conditions
Keywords
Vaginal Testosterone Cream, ESTRING
Brief summary
The purpose of this clinical research study is to determine whether the ESTRING or a special preparation of a testosterone cream inserted vaginally are safe for use in breast cancer patients. This study will also evaluate if either of these treatments can improve symptoms of vaginal dryness or decreased sexual interest that are related to your treatment for breast cancer.
Detailed description
There is a growing body of scientific literature to suggest that sexual functioning is one of the most distressing problems experienced by breast cancer survivors. Vaginal dryness, dyspareunia (pain during sexual intercourse), and decreased libido are common complaints among breast cancer patients. With increasing use of aromatase inhibitors which are associated with a higher rate of vaginal dryness than tamoxifen, these problems are becoming even more prominent. This study will evaluate the safety and tolerability of the ESTRING and 1% testosterone cream administered vaginally as treatments for vaginal dryness and/or decreased libido in women receiving an aromatase inhibitor for early stage breast cancer.
Interventions
DRUGTestosterone Cream
1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
DRUGEstring
2mg ring inserted vaginally once every 12 weeks
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed Stage I-III breast cancer who are taking an aromatase inhibitor as adjuvant hormonal therapy. Patient must have started the aromatase inhibitor at least 60 days prior to enrolling. 2. Postmenopausal estradiol levels at baseline as measured by standard laboratory analysis. * Patient may be rendered postmenopausal through the use of a GnRH agonist, but must have confirmed post-menopausal levels of serum estradiol on two lab tests at least one month apart. * If patient has been rendered post-menopausal by adjuvant chemotherapy but has had a period within the past 12 months, post-menopausal levels of serum estradiol must be documented on two lab tests at least 3 months apart. 3. Age ≥18 and ≤80 years old. 4. ECOG ≤1 5. Adequate hematologic, hepatic, and renal function as defined by: * Hgb ≥9 g/dL * Absolute neutrophil count (ANC)/absolute granulocyte count (AGC) ≥1500 cells/mm3 * Platelet count ≥100,000/mm3 * Serum creatinine ≤1.5 mg/dL * Total bilirubin ≤1.5 times the ULN; and aspartate aminotransferase ≤3 times the ULN 6. Normal thyroid function tested within the past 6 months (Patients with a diagnosis of hypothyroidism and on thyroid supplementation must have had thyroid function tests in the normal range within the past 3 months) 7. Patient must have recovered from the side effects of previous chemotherapy, surgery, or radiation therapy for early breast cancer.
Exclusion criteria
1. History of radiation to the vaginal area 2. Concurrent treatment with any type of oral, injectable or topical form of estrogen or androgen therapy including natural supplements marketed as hormone replacement products 3. Initiation of topical moisturizers (for example, Replens), or herbal or alternative medicines to manage the symptoms of vaginal dryness while on study. Patients who were previously using these products may continue them with the same usage pattern while on study. 4. Use of vaginal hormonal products (rings, inserts, creams, gels) containing estrogens or androgens within the past 30 days. 5. History of an abnormal pap smear within the last 12 months 6. History of endometrial or ovarian cancer 7. Any episode of vaginal bleeding in the past 6 months that has not been evaluated by a gynecological exam and/or pelvic ultrasound 8. History of sexual dysfunction prior to diagnosis of breast cancer ( Sexual dysfunction will be defined as loss of libido or inability to achieve orgasm for which patient sought medical attention or which patient felt significantly interfered with quality of life.) 9. Moderate or severe depression for which the patient is receiving ongoing psychological counseling and/or taking antidepressants, and for whom, in the investigators opinion may be interfering in the patients sexual function independent of the side effects of breast cancer and aromatase inhibitor use. 10. Use of any investigational agent for breast cancer within 3 weeks of study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Persistently Elevated Serum Estradiol Level Outside the Post-menopausal Range | 12 Weeks | Liquid chromatography tandem mass spectrometry (Quest Diagnostics). Persistently elevated serum estradiol level outside the post-menopausal range was defined as: Serum estradiol \>10 pg/dl on two consecutive collections at least 4 weeks apart. 2. If baseline estradiol was \>10 pg/dl, subsequent levels \>10 pg/ml higher than baseline were considered a significant elevation outside the post-menopausal range. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Matched E2 by Commercial and Research (RIA) Analyses | baseline, 4 weeks | Serum estradiol assays sent to the UCSF clinical laboratory are sent out to Quest Diagnostics, which uses LC/MS for their ultra-sensitive estradiol assay. Samples were also sent to a specialized research lab in England which has developed an ultrasensitive assay using radioimmunoassay (RIA) after ether extraction (sensitivity limit of 3pmol/l) to quantify low levels of estradiol found in post-menopausal women |
| Total Testosterone Levels | 12 weeks | By serum ultrasensitive total testosterone test (Quest Diagnostics) |
| Serum Estradiol (E2) | 12 weeks | serial measurements of serum estradiol (E2) by liquid chromatography tandem mass spectrometry (Quest Diagnostics) |
| Sexual Satisfaction | Baseline, Week 4, Week 12 | Participants were asked to respond to a Sexual Satisfaction One Item Measure which asked Overall, how satisfactory to you is your sexual relationship with your partner? Response options range from 1 (Extremely unsatisfactory) to 6 (Extremely satisfactory). |
| Change in Vaginal Epithelium Scores | Baseline, 12 weeks | During a gynecologic exam, the vaginal epithelium was assessed by an examiner using the Vaginal Atrophy Scoring Scale to evaluate Rugae (lack of), Pallor (pinkness), Petechiae, Mucosal thinning, Dryness. Scores range from 0 (none) to 3 (severe); higher scores indicate less favorable outcomes. |
| Sexual Quality of Life | Baseline, Week 4, Week 12 | Cancer Rehabilitation Evaluation System (CARES) Sexual Dysfunction (SD) and Sexual Interest (SI) Subscales range from 0 to 4 and measure the severity of problems, with higher scores indicating more difficulty. |
Countries
United States
Participant flow
Pre-assignment details
Of 76 enrolled participants, one participant consented and was assigned to ESTRING, but did not insert ESTRING prior to withdrawing from the study.
Participants by arm
| Arm | Count |
|---|---|
| Estring Estring 2mg ring inserted vaginally once every 12 weeks | 39 |
| Testosterone Cream Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment | 36 |
| Total | 75 |
Baseline characteristics
| Characteristic | Estring | Testosterone Cream | Total |
|---|---|---|---|
| Age, Continuous | 56 years | 57 years | 56 years |
| Region of Enrollment United States | 39 participants | 36 participants | 75 participants |
| Sex: Female, Male Female | 39 Participants | 36 Participants | 75 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 39 | 10 / 36 |
| serious Total, serious adverse events | 0 / 39 | 0 / 36 |
Outcome results
Primary
Persistently Elevated Serum Estradiol Level Outside the Post-menopausal Range
Liquid chromatography tandem mass spectrometry (Quest Diagnostics). Persistently elevated serum estradiol level outside the post-menopausal range was defined as: Serum estradiol \>10 pg/dl on two consecutive collections at least 4 weeks apart. 2. If baseline estradiol was \>10 pg/dl, subsequent levels \>10 pg/ml higher than baseline were considered a significant elevation outside the post-menopausal range.
Time frame: 12 Weeks
Population: Per protocol, to be considered evaluable for the Primary Outcome, patients must complete both baseline evaluation and week 4 safety blood draw. 1 participant in the Testosterone arm was not evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Estring | Persistently Elevated Serum Estradiol Level Outside the Post-menopausal Range | 0 participants |
| Testosterone Cream | Persistently Elevated Serum Estradiol Level Outside the Post-menopausal Range | 4 participants |
Secondary
Change in Vaginal Epithelium Scores
During a gynecologic exam, the vaginal epithelium was assessed by an examiner using the Vaginal Atrophy Scoring Scale to evaluate Rugae (lack of), Pallor (pinkness), Petechiae, Mucosal thinning, Dryness. Scores range from 0 (none) to 3 (severe); higher scores indicate less favorable outcomes.
Time frame: Baseline, 12 weeks
Population: Patients with both baseline and week 12 gynecologic exams for evaluation of vaginal atrophy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estring | Change in Vaginal Epithelium Scores | Pallor | -0.88 units on a scale | Standard Deviation 0.84 |
| Estring | Change in Vaginal Epithelium Scores | Mucosal thinning | -0.62 units on a scale | Standard Deviation 0.49 |
| Estring | Change in Vaginal Epithelium Scores | Petechiae | -1.0 units on a scale | Standard Deviation 1.07 |
| Estring | Change in Vaginal Epithelium Scores | Dryness | -1.03 units on a scale | Standard Deviation 0.8 |
| Estring | Change in Vaginal Epithelium Scores | Rugae | -1.03 units on a scale | Standard Deviation 0.8 |
| Testosterone Cream | Change in Vaginal Epithelium Scores | Dryness | -0.71 units on a scale | Standard Deviation 0.91 |
| Testosterone Cream | Change in Vaginal Epithelium Scores | Rugae | -0.71 units on a scale | Standard Deviation 0.84 |
| Testosterone Cream | Change in Vaginal Epithelium Scores | Pallor | -0.91 units on a scale | Standard Deviation 0.75 |
| Testosterone Cream | Change in Vaginal Epithelium Scores | Petechiae | -0.74 units on a scale | Standard Deviation 1.38 |
| Testosterone Cream | Change in Vaginal Epithelium Scores | Mucosal thinning | -0.88 units on a scale | Standard Deviation 0.64 |
Comparison: Differences in rugae, pallor, petechiae, mucosal thinning and dryness between baseline and week 12p-value: <0.001t-test, 2 sided
Comparison: Differences in rugae, pallor, mucosal thinning, and dryness from baseline to 12 weeksp-value: <0.001t-test, 2 sided
Comparison: Difference in petechiae between baseline and week 12p-value: 0.0061t-test, 2 sided
Secondary
Matched E2 by Commercial and Research (RIA) Analyses
Serum estradiol assays sent to the UCSF clinical laboratory are sent out to Quest Diagnostics, which uses LC/MS for their ultra-sensitive estradiol assay. Samples were also sent to a specialized research lab in England which has developed an ultrasensitive assay using radioimmunoassay (RIA) after ether extraction (sensitivity limit of 3pmol/l) to quantify low levels of estradiol found in post-menopausal women
Time frame: baseline, 4 weeks
Population: Patients from both study arms arms with matched pairs of baseline and week 4 E2 performed by both commercial and research labs
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estring | Matched E2 by Commercial and Research (RIA) Analyses | Baseline E2 | 17.7 pg/ml | Standard Deviation 28.5 |
| Estring | Matched E2 by Commercial and Research (RIA) Analyses | 4-week E2 | 7.8 pg/ml | Standard Deviation 15 |
| Testosterone Cream | Matched E2 by Commercial and Research (RIA) Analyses | Baseline E2 | 17.9 pg/ml | Standard Deviation 44.1 |
| Testosterone Cream | Matched E2 by Commercial and Research (RIA) Analyses | 4-week E2 | 2.9 pg/ml | Standard Deviation 13.4 |
Comparison: Comparison of baseline estradiol between LC/MS and RIAp-value: >0.05t-test, 2 sided
Comparison: Comparison of week 4 estradiol between LC/MS and RIAp-value: >0.05t-test, 2 sided
Secondary
Serum Estradiol (E2)
serial measurements of serum estradiol (E2) by liquid chromatography tandem mass spectrometry (Quest Diagnostics)
Time frame: 12 weeks
Population: Per protocol, participants who completed 12 weeks of assigned treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estring | Serum Estradiol (E2) | E2 at 12 weeks | 9 pg/ml | Standard Deviation 12 |
| Estring | Serum Estradiol (E2) | E2 at baseline | 27 pg/ml | Standard Deviation 36 |
| Estring | Serum Estradiol (E2) | E2 at 4 weeks | 5 pg/ml | Standard Deviation 5 |
| Testosterone Cream | Serum Estradiol (E2) | E2 at 4 weeks | 10 pg/ml | Standard Deviation 20 |
| Testosterone Cream | Serum Estradiol (E2) | E2 at 12 weeks | 8 pg/ml | Standard Deviation 7 |
| Testosterone Cream | Serum Estradiol (E2) | E2 at baseline | 9 pg/ml | Standard Deviation 13 |
Secondary
Sexual Quality of Life
Cancer Rehabilitation Evaluation System (CARES) Sexual Dysfunction (SD) and Sexual Interest (SI) Subscales range from 0 to 4 and measure the severity of problems, with higher scores indicating more difficulty.
Time frame: Baseline, Week 4, Week 12
Population: Participants who provided responses to SD, SI and SS at 3 time points: Baseline (BL), Week 4 (W4), and Week 12 (W12)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estring | Sexual Quality of Life | SI (W4) | 1.3 units on a scale | Standard Deviation 1 |
| Estring | Sexual Quality of Life | SD (BL) | 2.9 units on a scale | Standard Deviation 1.1 |
| Estring | Sexual Quality of Life | SI (W12) | 0.9 units on a scale | Standard Deviation 0.7 |
| Estring | Sexual Quality of Life | SI (BL) | 1.2 units on a scale | Standard Deviation 0.9 |
| Estring | Sexual Quality of Life | SD (W4) | 2.4 units on a scale | Standard Deviation 1.1 |
| Estring | Sexual Quality of Life | SD (W12) | 2.0 units on a scale | Standard Deviation 1.1 |
| Testosterone Cream | Sexual Quality of Life | SD (W4) | 2.1 units on a scale | Standard Deviation 1 |
| Testosterone Cream | Sexual Quality of Life | SD (W12) | 1.9 units on a scale | Standard Deviation 1.1 |
| Testosterone Cream | Sexual Quality of Life | SI (BL) | 1.4 units on a scale | Standard Deviation 0.8 |
| Testosterone Cream | Sexual Quality of Life | SI (W4) | 1.2 units on a scale | Standard Deviation 0.7 |
| Testosterone Cream | Sexual Quality of Life | SD (BL) | 2.9 units on a scale | Standard Deviation 0.8 |
| Testosterone Cream | Sexual Quality of Life | SI (W12) | 1.0 units on a scale | Standard Deviation 0.6 |
Comparison: Change in SI from BL to W12p-value: 0.021t-test, 2 sided
Comparison: Change in SD from BL to W12p-value: <0.001t-test, 2 sided
Comparison: Change in SI from BL to W12p-value: 0.0228t-test, 2 sided
Comparison: Change in SD from BL to W12p-value: <0.001t-test, 2 sided
Secondary
Sexual Satisfaction
Participants were asked to respond to a Sexual Satisfaction One Item Measure which asked Overall, how satisfactory to you is your sexual relationship with your partner? Response options range from 1 (Extremely unsatisfactory) to 6 (Extremely satisfactory).
Time frame: Baseline, Week 4, Week 12
Population: Participants who provided responses to SD, SI and SS at all 3 time points: Baseline (BL), Week 4 (W4), and Week 12 (W12)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estring | Sexual Satisfaction | SS (BL) | 2.5 units on a scale | Standard Deviation 1.6 |
| Estring | Sexual Satisfaction | SS (W4) | 3.5 units on a scale | Standard Deviation 1.8 |
| Estring | Sexual Satisfaction | SS (W12) | 4.0 units on a scale | Standard Deviation 1.5 |
| Testosterone Cream | Sexual Satisfaction | SS (BL) | 3.2 units on a scale | Standard Deviation 1.6 |
| Testosterone Cream | Sexual Satisfaction | SS (W4) | 3.7 units on a scale | Standard Deviation 1.6 |
| Testosterone Cream | Sexual Satisfaction | SS (W12) | 4.0 units on a scale | Standard Deviation 1.5 |
Comparison: Change in SS from Baseline to Week 12p-value: 0.004t-test, 2 sided
Comparison: Change in SS from Baseline to Week 12p-value: 0.139t-test, 2 sided
Secondary
Total Testosterone Levels
By serum ultrasensitive total testosterone test (Quest Diagnostics)
Time frame: 12 weeks
Population: Per protocol, participants assigned to the Testosterone arm who completed 12 weeks of assigned treatment and had testosterone measurement at baseline, 4 weeks and 12 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estring | Total Testosterone Levels | Testosterone at baseline | 33 ng/dl | Standard Deviation 19 |
| Estring | Total Testosterone Levels | Testosterone at 4 weeks | 186 ng/dl | Standard Deviation 276 |
| Estring | Total Testosterone Levels | Testosterone at 12 weeks | 171 ng/dl | Standard Deviation 251 |