Testosterone Effects on Pelvic Floor Muscles (TPELVIC)

A Pilot Study To Evaluate The Effect of Testosterone Enanthate On Structural and Functional Characteristics of Pelvic Floor Muscles In Postmenopausal Women With Urinary Incontinence

An proof-of-concept study to determine whether administration of testosterone enanthate weekly results in greater improvements in structural and functional characteristics of pelvic floor muscles and urodynamic parameters in postmenopausal women with urinary incontinence than that associated with placebo administration

Study Overview

• Status: Withdrawn
• Conditions: Urinary Incontinence; Menopause
• Intervention / Treatment: Drug: Testosterone Enanthate; Drug: Placebo

Detailed Description

Androgen therapy has been widely promoted in women with low serum testosterone levels for the treatment of sexual dysfunction and also for potentially improving body composition, muscle performance, bone mineral density and cognition. Androgens are known to exert direct anabolic effects on skeletal muscle. Testosterone supplementation results in dose-dependent increases in both muscle mass and strength in men. Similarly, our group has also demonstrated that 24-weeks of testosterone administration in hysterectomized women with low testosterone levels was associated with dose and concentration-dependent gains in lean body mass, chest-press power and loaded stair-climb power. Given that androgen receptors have been shown to be expressed throughout the pelvic floor and lower urinary tract, the anabolic effects of androgens on pelvic floor muscles and urethral sphincter may provide a therapeutic option in women with urinary incontinence.

In spite of the recognition of the important role of androgens in regulation of pelvic floor muscle mass and function, no randomized trials of the effects of testosterone or selective androgen receptor modulators have been published. Towards our long-term goal of conducting such a randomized efficacy trial of the effect of androgens in women with urinary incontinence, this initial pilot study will provide important data as a proof-of-the concept that the mass and function of levator ani and other pelvic floor muscles can be increased meaningfully by administration of testosterone, and that the increase in the mass and function of pelvic floor muscles will be associated with significant improvements in urodynamic parameters. Although MRI has been used clinically to evaluate pelvic floor anatomy, dynamic MRI of the pelvic floor muscles coupled with urodynamic studies has not been standardized previously; an important aim of this pilot study is to optimize the procedures for dynamic MR imaging of the pelvic floor structures and couple them with evaluation of urodynamics of the urinary bladder, bladder sphincter, and the urethra. Furthermore, the preliminary estimates of effect size and variance generated in this pilot study will guide the estimates of sample size and statistical power in subsequent larger randomized efficacy trials of androgens in women with urinary incontinence.

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 58 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Medically stable, ambulatory, postmenopausal women, 60 years of age or older
2. A normal mammogram in the preceding 12 months of study entry will be required. Women will be asked to either provide documentation of their last mammogram results or, with their permission, sign a medical release form to allow us to obtain the results of their last mammogram.
3. Able to give informed consent
4. Women with either stress urinary incontinence, or mixed urinary incontinence (stress and urgency)

Exclusion Criteria:

1. Women with endometrial stripe >4 mm on pelvic ultrasound
2. ≥ 1 first-degree relative with breast cancer
3. Previous pelvic surgery (ie. hysterectomy)
4. Women with history of radiation treatment to the pelvis
5. Any neurologic disorder causing urinary incontinence or bladder dysfunction (ie. multiple sclerosis)
6. Estrogen therapy currently or in the past 3 months
7. Women who have been diagnosed with major psychoses or bipolar disorders and/or untreated depression
8. Women with severe depression and/or severe anxiety as measured by the Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI), respectively
9. Any acute or subacute illness that required hospitalization in the last three months
10. Cancers that require active therapy (not in remission for at least two years) including those with a life expectancy less than 5 years
11. Poorly controlled diabetes mellitus (hemoglobin A1c greater than 8.0%). Subjects on insulin therapy will be excluded.
12. Uncontrolled hypertension defined as an average of two blood pressure readings of greater than 160/100
13. Severe obesity defined as body mass index of greater than 40 kg/m2
14. Current or recent (last 6 months) users of illicit drugs
15. Significant liver function abnormalities, defined as SGOT, SGPT or alkaline phosphatase value of greater than 1.5 times the upper limit of normal or serum bilirubin levels of greater than 1.5 mg/dl will be excluded
16. History of breast, ovarian, or endometrial cancer.
17. History of hyperandrogenic disorders such as moderate to severe hirsutism and/or acne (by self-report), and polycystic ovary disease. Testosterone administration to these patients may exacerbate the underlying disorder.
18. Significant acne, defined as grade 3 on Palatsi Acne Scale
19. Women with a mammogram that requires follow-up every 3-6 months, or those who have any first-degree relatives with breast cancer will be excluded.
20. Women with history of a major cardiovascular event, including angina, congestive heart failure, cerebral vascular accident or history of myocardial infarction or coronary artery angioplasty or bypass surgery
21. Other Medications. Women who have received in the preceding three months drugs known to affect testosterone production or metabolism such as ketoconazole, Megace, anabolic/androgenic steroids for 3 weeks or longer will be excluded. Women taking ≥ 7.5 mg of prednisone or equivalent glucocorticoid dosing will be excluded. We will also exclude women who are taking or have taken in the past three months medications that affect sexual function (e.g., spironolactone, GnRH agonists). Women receiving thyroid hormone replacement therapy may participate in the study if they have been on a stable replacement dose of L-thyroxine for at least six months.
22. Undiagnosed vaginal or vulvar bleeding
23. Women taking concurrent anticoagulants or how have bleeding disorders
24. History of deep vein thrombosis, pulmonary embolism, or other thromboembolic disorder
25. Current enrollment in clinical drug intervention studies in the preceding 90 days
26. Hematocrit < 30% or >48% (Since hematocrit values can transiently increase as a result of dehydration, and the subjects in this trial are required to come after an overnight fast, hematocrit levels may be repeated once if the investigators determine that the initial elevated hematocrit was influenced by dehydration)
27. Women who have previously experienced intolerance to testosterone enanthate injections
28. Unable to undergo MRI of the pelvis (e. g. body containing any metallic medical devices or equipment, including heart pacemakers, metal prostheses, implants or surgical clips, any prior injury from shrapnel or grinding metal, exposure to metallic dusts, metallic shavings or having tattoos containing metallic dyes).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment Arm; weekly IM administration of 25 mg Testosterone Enanthate for 12 weeks	Drug: Testosterone Enanthate; 25 mg testosterone enanthate administered by intramuscular injection weekly for 12 weeks; Other Names: Delatestryl
Placebo Comparator: Control Arm; Weekly IM administration of placebo for 12 weeks	Drug: Placebo; Placebo administered by intramuscular injection weekly for 12 weeks; Other Names: Inactive comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pelvic floor muscle volume	Pelvic floor muscle volume will be measured by 3-dimensional dynamic pelvic floor magnetic resonance imaging (MRI)	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in urine volume at first desire to void	Urine volume at first desire to void will be assessed by cystometry	12 weeks
Change in urine volume at first urge to void	Urine volume at first urge to void will be assessed by cystometry	12 weeks
Change in maximum cystometric capacity (when the patient feels she can no longer delay micturition)	Maximum Cystometric Capacity will be assessed by cystometry	12 weeks
Change in urine flow	Rate of urine flow (urine volume voided over time) will be assessed by Uroflowmetry	12 weeks
Change in urethral sphincter contraction strength	Strength of urethral sphincter contraction will be assessed by urethral pressure profilometry.	12 weeks
Change in urine leak point pressure	Urine leak point pressure will be assessed by cystometry	12 weeks
Change in self-reported urinary incontinence	Urinary Incontinence will be assessed by the Urogenital Distress Inventory (UDI-6 Short Form). The UDI-6 Short Form is a questionnaire with 6 questions that assess the presence and severity of urinary incontinence symptoms. Each question has a potential score of 1 to 4. The final UDI-6 score is calculated by adding all scores as explained above, and dividing the result by 6 to obtain a mean value which is in turn multiplied by 25 to obtain the scale score. The total scaled score can range from 0 to 100, higher scores indicating more severe urinary incontinence, and lower scores indicating less severe urinary incontinence	12 weeks

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Grace Huang, MD, Partners Health Care, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Huang G, Basaria S, Travison TG, Ho MH, Davda M, Mazer NA, Miciek R, Knapp PE, Zhang A, Collins L, Ursino M, Appleman E, Dzekov C, Stroh H, Ouellette M, Rundell T, Baby M, Bhatia NN, Khorram O, Friedman T, Storer TW, Bhasin S. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance and physical function in a randomized trial. Menopause. 2014 Jun;21(6):612-23. doi: 10.1097/GME.0000000000000093.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2021
• Primary Completion (Anticipated): January 1, 2022
• Study Completion (Anticipated): June 1, 2022

Study Registration Dates

• First Submitted: July 17, 2019
• First Submitted That Met QC Criteria: July 18, 2019
• First Posted (Actual): July 19, 2019

Study Record Updates

• Last Update Posted (Actual): July 20, 2022
• Last Update Submitted That Met QC Criteria: July 18, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Menopause; Urinary Incontinence; Androgens; Pelvic Floor Muscles
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Urologic Diseases; Lower Urinary Tract Symptoms; Urological Manifestations; Urination Disorders; Elimination Disorders; Urinary Incontinence; Enuresis; Physiological Effects of Drugs; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Androgens; Anabolic Agents; Testosterone; Methyltestosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
• Other Study ID Numbers: 2018P000248

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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